Input: What is the main advantage of a horizontal business model for mobile devices?

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The future of mobile CPUs, part 1: Today’s fork in the road | Ars Technica
2013 may be a big year for the evolution of smartphones and tablets.
Mobile computing's rise from niche market to the mainstream is among the most significant technological trends in our lifetimes. And to a large extent, it's been driven by the bounty of Moore’s Law—the rule that transistor density doubles every 24 months. Initially, most mobile devices relied on highly specialized hardware to meet stringent power and size budgets. But with so many transistors available, devices inevitably grew general-purpose capabilities. Most likely, that wasn't even the real motivation. The initial desire was probably to reduce costs by creating a more flexible software ecosystem with better re-use and faster time to market. As such, the first smartphones were very much a novelty, and it took many years before the world realized the potential of such devices. Apple played a major role by creating innovative smartphones that consumers craved and quickly adopted.
To some extent, this is where we still stand today. Smartphones are still (relatively) expensive and primarily interesting to the developed world. But over the next 10 years, this too will change. As Moore’s Law rolls on, the cost of a low-end smartphone will decline. At some point, the incremental cost will be quite minimal and many feature phones of today will be supplanted by smartphones. A $650 unsubsidized phone is well beyond the reach of most of the world compared to a $20 feature phone, but a $30 to $40 smartphone would naturally be very popular.
In this grand progression, 2013 will certainly be a significant milestone for mobile devices, smartphones and beyond. It's likely to be the first year in which tablets out-ship notebooks in the US. And in the coming years, this will lead to a confluence of high-end tablets and ultra-mobile notebooks as the world figures out how these devices co-exist, blend, hybridize, and/or merge.
Against this backdrop, in this two-part series, we'll explore the major trends and evolution for mobile SoCs. More importantly, we'll look to where the major vendors are likely going in the next several years.
Tablet and phone divergence
While phones and tablets are mobile devices that often share a great deal of software, it's becoming increasingly clear the two are very different products. These two markets have started to diverge and will continue doing so over time.
From a technical perspective, smartphones are far more compact and power constrained. Smartphone SoCs are limited to around 1W, both by batteries and by thermal dissipation. The raison d’etre of a smartphone is connectivity, so a cellular modem is an absolute necessity. For the cost sensitive-models that make up the vast majority of the market, the modem is integrated into the SoC itself. High-end designs favor discrete modems with a greater power budget instead. The main smartphone OSes today are iOS and Android, though Windows is beginning to make an appearance (perhaps with Linux or BlackBerry on the horizon). Just as importantly, phone vendors like HTC must pass government certification and win the approval of carriers. There is very much a walled-garden aspect, where carriers control which devices can be attached to their networks, and in some cases devices can only be sold through a certain carrier. The business model places consumers quite far removed from the actual hardware.
In contrast, tablets are far more akin to the PC both technically and economically. The power budget for tablet SoCs is much greater, up to 4W for a passively cooled device and as high as 7-8W for systems with fans. This alone means there is a much wider range of tablet designs than smartphones. Moreover, the default connectivity for tablets is Wi-Fi rather than a cellular modem. The vast majority of tablets do not have cellular modems, and even fewer customers actually purchase a wireless data plan. As a result, cellular modems are almost always optional discrete components of the platform. The software ecosystem is relatively similar, with Microsoft, Apple, and Google OSes available. Because tablets eschew cellular modems, the time to market is faster, and they are much more commonly sold directly to consumers rather than through carriers. In terms of usage models, tablets are much more PC-like, with reasonable-sized screens that make games and media more attractive.
Looking forward, these distinctions will likely become more pronounced. Many tablets today use high-end smartphone SoCs, but the difference in power targets and expected performance is quite large. As the markets grow in volume, SoCs will inevitably bifurcate to focus on one market or the other. Even today, Apple is doing so, with the A6 for phones and the larger A6X for tablets. Other vendors may need to wait a few years to have the requisite volume, but eventually the two markets will be clearly separate.
Horizontal business model evolution
Another aspect of the mobile device market that is currently in flux and likely to change in the coming years is the business model for the chip and system vendors. Currently, Apple is the only company truly pursuing a vertically integrated model, where all phones and tablets are based on Apple’s own SoC designs and iOS. The tight integration between hardware and software has been a huge boon for Apple, and it has yielded superb products.
Samsung is one of the few others companies that takes a vertically integrated approach to phones and tablets, although in truth its strategy seems to be ambivalent on that point. Unlike Apple, Samsung’s SoCs are readily available to third parties, and some Samsung devices, such as the S7562 Galaxy S Duos, use SoCs from competitors. More recently though, there has been a trend of Samsung devices using Samsung SoCs, at least for the premier products. For the moment, Samsung’s approach is best characterized as a hybrid, particularly as the company lacks a bespoke OS.
The rest of the major SoC vendors (e.g., Intel, Qualcomm, Nvidia, TI, Mediatek, etc.) have stayed pretty far away from actual mobile devices. These companies tend to focus on horizontal business models that avoid competing with customers or suppliers.
In the long term, mobile devices are likely to evolve similarly to the PC and favor a horizontal business model. The real advantage is one of flexibility; as costs drop and the market expands, it will be increasingly necessary for vendors like HTC to offer a wide range of phones based on radically different SoCs. While a vertically integrated company like Apple can focus and maintain leadership in a specific (and highly lucrative) niche, it would be very difficult to expand in many growing areas of the market. The differences between an iPhone 6 and a $20 feature phone are tremendous and would be very difficult for a single company to bridge.
However, SoC vendors will attempt to reap the benefits of vertical integration by providing complete reference platforms to OEMs. Conceptually, this is a form of "optional" system integration, where the phone vendor or carrier can get the entire platform from the SoC supplier. This has the principal advantages of reducing time to market while also providing a baseline quality and experience for consumers. Currently, this approach has mostly been tested in emerging markets, but it's likely to become more common over time. There is a crucial distinction between reference platforms and vertical integration. Namely, OEMs can always choose to customize a platform to differentiate, and the SoC vendor avoids dealing with consumers directly. Typically, most of the customization is in terms of software on top of a base operating system.
Quote:Moreover, that will make the transition to a 10nm node even more difficult, as the foundries will have to move from 20nm interconnects to 10nm interconnects and skip a generation.The advances in technology lately allowing components on such a small scale to even be envisioned, much less planned for, are truly amazing.
Off topic: show
I present the first generation 'non-technical' rock:
I don't think your horizontal market development theory is supported by facts. Samsung and Apple are more vertically oriented than their competition, for starters. I know this article is narrowly focused on the hardware, but MS and Intel getting into hardware, Amazon getting into hardware, Google buying Moto, this is all vertical integration. How can you support the idea that this trend will be reversed with no real justification? I'm sure mobile chips will continue to specialize, but I don't think this means what you think it means. Automobile companies started making their own engines and with rare exceptions, never went back to being more horizontal. Same with retail and their store brands. Same with cloud companies and their servers. Same with mobile companies and their OSs. The horizontal market of PCs created by long-lasting standards and loose hegemony is the exception, not the norm.
Why wouldn't the foundries be able close the process gap with Intel? Is it a matter of money? Scale?
I'm not so sure about several things:1- Moore's law's relevance. Moore's Law is about ICs. ICs are not as big a part of mobile computers as they are of desktops, even of laptops: screens, batteries, radios are a huge part of tablets' and phones' costs, as opposed to the bare SoC + RAM.2- The tablet vs phone dichotomy. For some reason (probably price insensitivity due to subsidies), Phones have a tendency to be more powerful than Tablets, ie phone SoCs are more than good enough for tablets. Since the OS and peripherals are the same, it makes more sense to design and build just one type of SoC, and just disable the phone-modem part of it (even the other radios are still required: BT, Wifi, GPS...), same as Intel disable cache and cores for their entry-level CPUs. Once you're fabbing a SoC, it makes more sense to make more of the same than to setup a separate run of a cut-down SoC on an older process, unless volumes are huge. We might still be getting previous-generation, well amortized SoCs in cheaper tablets, though.3- On the contrary, I see a tablet and phone convergence (the ugly phablet). I'm patiently waiting for the new 6"+ phones to replace my Nook Color and Galaxy Note 1 with a single device.4- The advantage of diversity ? Software is becoming ever more important than hardware. Multiplying SoCs means multiplying product development costs, making support and updates more difficult... Again, unless volumes are huge, OEMs are probaly better off going the way of the car industry and using modular "platforms" housed in different chassis with various screen sizes, keyboards, radios, digitizers...I'm wondering why the "single device" trend does not figure in your analysis. Is it stillborn ? Does it have no impact nor dependency on/with SoCs ?
Samsung has its own bespoke OS: Bada and it is used on an extensive line of devices. I think there are numbers somewhere that it outsold Windows Phone 7 for a time.
gypsumfantastic wrote:Why wouldn't the foundries be able close the process gap with Intel? Is it a matter of money? Scale?First mover advantage.
SoC? System on a Chip I guess?
You're way off on the Moore's Law/cost of smartphones point. The processors used in today's high-end smartphones are already cheap, around $25. And there are less expensive options if you want a lower end product. In fact, the hardware in the whole smartphone is relatively cheap. Analyst's estimate the Z10's materials cost around $160, the iPhone 5 around $140. They're using expensive glass and metals, then there's the battery, memory, etc. which means the processor is a small factor of the cost.And then there's the jump from $140 in materials to the unsubsidized costs. The reason these phones cost $650 is because of the high margins these companies are able to get and the high cost of hardware design and/or software development. But the point is that making the processors 4 times better/cheaper isn't going to change the economics of the smartphone. What will change the economics is commoditized designs and software and cheaper materials all around. Then you'll have a $50 smartphone that's decent.
Last edited by ggeezz on Wed Feb 13, 2013 9:17 am
bigterp wrote:SoC? System on a Chip I guess?Yup.
gypsumfantastic wrote:Why wouldn't the foundries be able close the process gap with Intel? Is it a matter of money? Scale?Money and momentum, the x86 market is a huge money maker for Intel so it is able to recoup its huge investments for advanced foundries.
Quote:Currently, the only products using 3D integration are FPGAs from Xilinx,Doesn't Sony use it in the PS Vita? I thought I read somewhere that they had the CPU, main memory (2 dies) and video memory, so 4 dies in total, sitting on top of each other all on the same chip.
renoX wrote:gypsumfantastic wrote:Why wouldn't the foundries be able close the process gap with Intel? Is it a matter of money? Scale?Money and momentum, the x86 market is a huge money maker for Intel so it is able to recoup its huge investments for advanced foundries.Exactly and I would clarify that it's all about margins, the difference between what it costs to make a chip and what it sells for. The margins for desktop and server processors is huge because a) the whole product is expensive so $200 to $1000 for the chip is acceptable, and b) Intel has huge advantages in that space and little competition.So Intel can afford to do the R&D to stay ahead of the curve and keep their position. When your smartphone chip sells for $25 you can't do the R&D to leapfrog a company that sells Xeons for $1000 and Core i5's for $200.
I am happy to see Kanter here at Ars, I like his writing and he maintains Real World Tech, where Linus Torvalds often shows up to comment on CPU arch and other interesting topics.
ggeezz wrote:renoX wrote:gypsumfantastic wrote:Why wouldn't the foundries be able close the process gap with Intel? Is it a matter of money? Scale?Money and momentum, the x86 market is a huge money maker for Intel so it is able to recoup its huge investments for advanced foundries.Exactly and I would clarify that it's all about margins, the difference between what it costs to make a chip and what it sells for. The margins for desktop and server processors is huge because a) the whole product is expensive so $200 to $1000 for the chip is acceptable, and b) Intel has huge advantages in that space and little competition.So Intel can afford to do the R&D to stay ahead of the curve and keep their position. When your smartphone chip sells for $25 you can't do the R&D to leapfrog a company that sells Xeons for $1000 and Core i5's for $200.Spot on.Intel are able to piggyback other development efforts off the highly lucrative mainstream x86 market which generates the huge sums of money to fund their amazing fab technology.The question for the future is how the economics will stack up when overall device costs fall significantly and there is a big downward pressure on SoC prices. In that situation, can Intel still justify bringing their A-game to a market where products are essentially commoditised and you have processors selling for a only a few dollars each?The lesson from their previous involvement in the DRAM market is that they probably won't want to be involved because there isn't enough money to be made to justify manufacturing phone SoCs on a cutting edge, or near cutting edge process. In that scenario, Intel may not totally abandon the market but they might just stick to manufacturing SoCs on nodes that are a step or two behind the state of the art.
solomonrex wrote:I don't think your horizontal market development theory is supported by facts. Samsung and Apple are more vertically oriented than their competition, for starters. I know this article is narrowly focused on the hardware, but MS and Intel getting into hardware, Amazon getting into hardware, Google buying Moto, this is all vertical integration. How can you support the idea that this trend will be reversed with no real justification? I'm sure mobile chips will continue to specialize, but I don't think this means what you think it means. Automobile companies started making their own engines and with rare exceptions, never went back to being more horizontal. Same with retail and their store brands. Same with cloud companies and their servers. Same with mobile companies and their OSs. The horizontal market of PCs created by long-lasting standards and loose hegemony is the exception, not the norm.Yea, each year Amazon, MS, Apple and Google look more and more the same.
Intel cannot abandon the phone/tablet market. Desktop/laptop sales are stagnating/decreasing and phones/tablets are on the rise. This trend is only going to increase going forward.But you're right, they're going to have use their fabs that are a step or two behind the cutting the edge. But they're going to have to up their game in the tablet space to even be able to do that.
gypsumfantastic wrote:Why wouldn't the foundries be able close the process gap with Intel? Is it a matter of money? Scale?Intel's called Chipzilla for a reason up
Lagrange wrote:The question for the future is how the economics will stack up when overall device costs fall significantly and there is a big downward pressure on SoC prices. In that situation, can Intel still justify bringing their A-game to a market where products are essentially commoditised and you have processors selling for a only a few dollars each?The lesson from their previous involvement in the DRAM market is that they probably won't want to be involved because there isn't enough money to be made to justify manufacturing phone SoCs on a cutting edge, or near cutting edge process. In that scenario, Intel may not totally abandon the market but they might just stick to manufacturing SoCs on nodes that are a step or two behind the state of the art.I think the processing is a bigger advantage than many realize. If Intel can stay ahead in process design - which this article seems to indicate - they should have a major advantage. All else being equal a 14nm chip should be significantly faster and more efficient than the same chip at 22nm. Add in the fact that yields increase geometrically - you can fit a lot more 14nm chips on a given wafer size vs 22nm (or 32nm for the other manufacturers.) and you have a very appealing proposition. And then add in the fact that Intel actually has a pretty good graphics stack and IP. It's not a sure thing by any means, but I suspect ARM may have just prodded a sleeping giant.edit: Also worth noting, Intel, TSMC, and Samsung are the only manufacturers who are building out 450nm wafers. This will increase yields dramatically. Of course Samsung and TSMC will build ARM out, but it definitely puts quite a bit of pressure on all other manufacturers. As the article mentions Intel and Samsung are the only ones who control production top to bottom, and Samsung must share some of the benefits with ARM.
As someone who has worked in the semiconductor industry for longer than contemporary fanboys have existed, I'm getting a bit fed-up seeing many of these articles which rewrite history with analyses distorted by the lens of the contemporary Apple or Samsung fanboy.The mobile industry moved to horizontal integration a long time ago. Better indicators than these odd contemporary obsessions with the relatively non-innovative Samsung and Apple where when Motorola spun out its semiconductor division as Freescale, Nokia stopped making it's own custom designs with TI and ST, and Ericsson spun out it's Ericsson Mobile Platforms division and formed ST-Ericsson with ST.The true innovation in the mobile market was done a decade or more ago mainly by Moto/Nokia/Ericsson/TI/Qualcomm, and Samsung and Apple had little to do with it. Under the hood most stuff has been on a simple linear evolutionary path by the SoC providers since then. The phone manufacturers have then mainly been simply sticking these off-the-shelf SoCs (and their included low-level software stacks) in a box, a job made all the easier with the SoC manufacturer collaboration providing the bulk of the work for the AOSP.
Last edited by paul5ra on Wed Feb 13, 2013 11:06 am
introiboad wrote:I am happy to see Kanter here at Ars, I like his writing and he maintains Real World Tech, where Linus Torvalds often shows up to comment on CPU arch and other interesting topics.Indeed. Most tech writing in this area is atrocious. This piece is one of the few well informed articles I've read in a long time.
ggeezz wrote:Intel cannot abandon the phone/tablet market. Desktop/laptop sales are stagnating/decreasing and phones/tablets are on the rise. This trend is only going to increase going forward.But you're right, they're going to have use their fabs that are a step or two behind the cutting the edge. But they're going to have to up their game in the tablet space to even be able to do that.The word you're looking for is Haswell, as far as I know.
Mabsark
ggeezz wrote:Intel cannot abandon the phone/tablet market. Desktop/laptop sales are stagnating/decreasing and phones/tablets are on the rise. This trend is only going to increase going forward.But you're right, they're going to have use their fabs that are a step or two behind the cutting the edge. But they're going to have to up their game in the tablet space to even be able to do that.Actually, that trend will not simply keep increasing going forward. The reason desktop/laptop sales are stagnating/decreasing is due to the fact that most people already have one and therefore don't need to buy another one. The exact same thing will happen with tablets as well. Sales are increasing now because people without tablets are buying them. When most people already own a tablet, they won't be buying a new one every year and therefore sales will stagnate/decrease.The PC market is saturated and in a couple of years, the tablet market will be saturated too. Basically, in order to increase sales in a saturated market, you need to increase the population growth or decrease the longevity of the product.
gypsumfantastic wrote:Why wouldn't the foundries be able close the process gap with Intel? Is it a matter of money? Scale?Probably a mix of a lot of things. One big thing was during this recession, Intel was the ONLY fab company that didn't scale back their R&D. That alone gave Intel a large advantage.Intel has almost always been ahead. One of the reasons could be that Intel works with much higher margins than many of the commodity companies like Samsung and TSMC.Outside of the P4 flop and some of the monopolistic abuses, Intel has typically been selling to high end customers that are willing to pay a premium for "the best".Intel has a large benefit of having a relatively "good name" when it comes to CPUs, so they can effectively charge a brand-name premium.I'm sure there are other reasons, and probably better reasons, but these are the main ones that I think of.
Mabsark wrote:Actually, that trend will not simply keep increasing going forward. The reason desktop/laptop sales are stagnating/decreasing is due to the fact that most people already have one and therefore don't need to buy another one. The exact same thing will happen with tablets as well. Sales are increasing now because people without tablets are buying them. When most people already own a tablet, they won't be buying a new one every year and therefore sales will stagnate/decrease.The PC market is saturated and in a couple of years, the tablet market will be saturated too. Basically, in order to increase sales in a saturated market, you need to increase the population growth or decrease the longevity of the product.That's true as long as most people are still buying both a tablet and a laptop when each needs to be replaced. I think the assumption is that, as you say, the tablet market will saturate, with people just replacing existing ones, but the desktop/laptop market could decrease much farther than that, if most people stop replacing them at all. I'm not sure of the likelihood of that, but I think that's where this idea comes from.
ggeezz wrote:Intel cannot abandon the phone/tablet market. Desktop/laptop sales are stagnating/decreasing and phones/tablets are on the rise. This trend is only going to increase going forward.But you're right, they're going to have use their fabs that are a step or two behind the cutting the edge. But they're going to have to up their game in the tablet space to even be able to do that.The upcoming Haswell chip is showing to consume 1/3 the power of IvyBridge at peak, consumes 1/20th the power at idle, all the while maintaining Identical or better performance.This chip should actually compete with ARM CPUs on both power/performance and idle.I am expecting a large war.
Apple once again is dictating the performance in the mobile industry. Nice to see others being able to keep the pace, as well.
paul5ra wrote:As someone who has worked in the semiconductor industry for longer than contemporary fanboys have existed, I'm getting a bit fed-up seeing many of these articles which rewrite history with analyses distorted by the lens of the contemporary Apple or Samsung fanboy.The mobile industry moved to horizontal integration a long time ago. Better indicators than these odd contemporary obsessions with the relatively non-innovative Samsung and Apple where when Motorola spun out its semiconductor division as Freescale, Nokia stopped making it's own custom designs with TI and ST, and Ericsson spun out it's Ericsson Mobile Platforms division and formed ST-Ericsson with ST.The true innovation in the mobile market was done a decade or more ago mainly by Moto/Nokia/Ericsson/TI/Qualcomm, and Samsung and Apple had little to do with it. Under the hood most stuff has been on a simple evolutionary path by the SoC providers since then.Yeah, and most of the innovation in the automobile industry came about before Henry Ford came into the business. Doesn't change the fact that cars would probably have been an asterisk in the history books under "toys for rich people" if it weren't for him.The same applies to to mobile computing for Apple, Samsung, et al.
SheldonRoss wrote:Lagrange wrote:The question for the future is how the economics will stack up when overall device costs fall significantly and there is a big downward pressure on SoC prices. In that situation, can Intel still justify bringing their A-game to a market where products are essentially commoditised and you have processors selling for a only a few dollars each?The lesson from their previous involvement in the DRAM market is that they probably won't want to be involved because there isn't enough money to be made to justify manufacturing phone SoCs on a cutting edge, or near cutting edge process. In that scenario, Intel may not totally abandon the market but they might just stick to manufacturing SoCs on nodes that are a step or two behind the state of the art.I think the processing is a bigger advantage than many realize. If Intel can stay ahead in process design - which this article seems to indicate - they should have a major advantage. All else being equal a 14nm chip should be significantly faster and more efficient than the same chip at 22nm. Add in the fact that yields increase geometrically - you can fit a lot more 14nm chips on a given wafer size vs 22nm (or 32nm for the other manufacturers.) and you have a very appealing proposition. And then add in the fact that Intel actually has a pretty good graphics stack and IP. My point was that Intel might have a one or two process advantage over the rest of the industry at the cutting edge but that doesn't mean that they can afford to manufacture on those processes for very low margin parts. If the SoC market becomes increasingly commoditised, there isn't going to be the money to justify making them in a state of the art fab.Remember that one of the big selling points of Itanium was that it would make use of process advantages that were effectively paid for by the mainstream x86 market. That didn't quite work out in practice and Itanium processors were often well behind Xeons in process technology.
paul5ra wrote:As someone who has worked in the semiconductor industry for longer than contemporary fanboys have existed, I'm getting a bit fed-up seeing many of these articles which rewrite history with analyses distorted by the lens of the contemporary Apple or Samsung fanboy.The mobile industry moved to horizontal integration a long time ago. Better indicators than these odd contemporary obsessions with the relatively non-innovative Samsung and Apple where when Motorola spun out its semiconductor division as Freescale, Nokia stopped making it's own custom designs with TI and ST, and Ericsson spun out it's Ericsson Mobile Platforms division and formed ST-Ericsson with ST.The true innovation in the mobile market was done a decade or more ago mainly by Moto/Nokia/Ericsson/TI/Qualcomm, and Samsung and Apple had little to do with it. Under the hood most stuff has been on a simple linear evolutionary path by the SoC providers since then. The phone manufacturers have then mainly been simply sticking these off-the-shelf SoCs (and their included low-level software stacks) in a box, a job made all the easier with the SoC manufacturer collaboration providing the bulk of the work for the AOSP.Just goes to show that people who have worked in an industry for a long time don't always understand what that industry is doing.You haven't been working in it long enough to seem to know that it was Acorn and Apple that invented the mobile ARM CPU in the first place. All those companies you've mentioned have just been working off Acorn and Apple's pioneering work. Now, Apple is back at it again, very successfully, and all the companies you mentioned that produce chips with ARM IP in them are licensing them from the company Acorn and Apple formed—ARM.
Last edited by melgross on Wed Feb 13, 2013 11:13 am
Mark Havel wrote:ggeezz wrote:Intel cannot abandon the phone/tablet market. Desktop/laptop sales are stagnating/decreasing and phones/tablets are on the rise. This trend is only going to increase going forward.But you're right, they're going to have use their fabs that are a step or two behind the cutting the edge. But they're going to have to up their game in the tablet space to even be able to do that.The word you're looking for is Haswell, as far as I know.If tablets move into the $100-200 range, is there going to be room for Haswell?So long as there is a higher-end tablet market, then Haswell will be able to shine, but it's going to be a much more powerful and costly part than the sort of ARM based hardware that often runs tablets. If we see a race to the bottom where price is the dominant motivator behind purchases, then a high performance SoC will struggle to make its mark.
melgross wrote:paul5ra wrote:As someone who has worked in the semiconductor industry for longer than contemporary fanboys have existed, I'm getting a bit fed-up seeing many of these articles which rewrite history with analyses distorted by the lens of the contemporary Apple or Samsung fanboy.The mobile industry moved to horizontal integration a long time ago. Better indicators than these odd contemporary obsessions with the relatively non-innovative Samsung and Apple where when Motorola spun out its semiconductor division as Freescale, Nokia stopped making it's own custom designs with TI and ST, and Ericsson spun out it's Ericsson Mobile Platforms division and formed ST-Ericsson with ST.The true innovation in the mobile market was done a decade or more ago mainly by Moto/Nokia/Ericsson/TI/Qualcomm, and Samsung and Apple had little to do with it. Under the hood most stuff has been on a simple linear evolutionary path by the SoC providers since then. The phone manufacturers have then mainly been simply sticking these off-the-shelf SoCs (and their included low-level software stacks) in a box, a job made all the easier with the SoC manufacturer collaboration providing the bulk of the work for the AOSP.Just goes to show that people who have worked in an industry for a long time don't always understand what that industry is doing.You haven't been working in it long enough to seem to know that it was Acorn and Apple that invented the mobile ARM CPU in the first place. All those companies you've mentioned have just been working off Acorn and Apple's pioneering work. Now, Apple is back at it again, very successfully, and all the companies you mentioned that produce chips with ARM IP in them are licensing them from the company Acorn and Apple formed—ARM.Of course I realise ARM IP has indeed been a major driving factor too (though only one if several architectures before ARM became dominant), though I see ARM's influence on the mobile industry as having nothing to do with modern day Apple and only one small piece of the puzzle. My point is that the hard electrical engineering, mathematics, DSP, semiconductor physics/chemistry, RF engineering, analogue design, CAD etc. that make modern telecommunications possible has very little to do with the fashion companies who consumers (and unfortunately much of the tech media) associate with it and give the credit (though in this respect Samsung does deserve a bit more credit for their work on NAND flash and displays). The industry simply would not exist TODAY without the overwhelming horizontal integration that already dominates.
Quote:In the long term, mobile devices are likely to evolve similarly to the PC and favor a horizontal business model. The real advantage is one of flexibility; as costs drop and the market expands, it will be increasingly necessary for vendors like HTC to offer a wide range of phones based on radically different SoCs. You don't mention in the article that each SoC necessarily requires a bit of parallel dev work unlike the PC. In the PC world there is a standard BIOS and HW architecture that allows for pluggable designs. On a highly integrated SoC this is untrue. HTC suffers because it has to support radically different SoCs, their drivers and boot loaders, etc. Quote:While a vertically integrated company like Apple can focus and maintain leadership in a specific (and highly lucrative) niche, it would be very difficult to expand in many growing areas of the market. The differences between an iPhone 6 and a $20 feature phone are tremendous and would be very difficult for a single company to bridge.It's only difficult because Apple chooses to ignore that market, not because they can't. If they can release a $99 Apple TV, they can surely cobble together a $20 feature phone if they chose to eschew 8GB of NAND, BT, WiFi, a specialized dock connector, LTE, and their specialized processors. In other words, build the equivalent of an iPod shuffle with a horrible screen and no OS to speak of.
paul5ra wrote:melgross wrote:paul5ra wrote:As someone who has worked in the semiconductor industry for longer than contemporary fanboys have existed, I'm getting a bit fed-up seeing many of these articles which rewrite history with analyses distorted by the lens of the contemporary Apple or Samsung fanboy.The mobile industry moved to horizontal integration a long time ago. Better indicators than these odd contemporary obsessions with the relatively non-innovative Samsung and Apple where when Motorola spun out its semiconductor division as Freescale, Nokia stopped making it's own custom designs with TI and ST, and Ericsson spun out it's Ericsson Mobile Platforms division and formed ST-Ericsson with ST.The true innovation in the mobile market was done a decade or more ago mainly by Moto/Nokia/Ericsson/TI/Qualcomm, and Samsung and Apple had little to do with it. Under the hood most stuff has been on a simple linear evolutionary path by the SoC providers since then. The phone manufacturers have then mainly been simply sticking these off-the-shelf SoCs (and their included low-level software stacks) in a box, a job made all the easier with the SoC manufacturer collaboration providing the bulk of the work for the AOSP.Just goes to show that people who have worked in an industry for a long time don't always understand what that industry is doing.You haven't been working in it long enough to seem to know that it was Acorn and Apple that invented the mobile ARM CPU in the first place. All those companies you've mentioned have just been working off Acorn and Apple's pioneering work. Now, Apple is back at it again, very successfully, and all the companies you mentioned that produce chips with ARM IP in them are licensing them from the company Acorn and Apple formed—ARM.Of course I realise ARM IP has indeed been a major driving factor too (though only one if several architectures before ARM became dominant), though I see ARM's influence on the mobile industry as having nothing to do with modern day Apple and only one piece of the puzzle. My point is that the hard electrical engineering, mathematics, DSP, semiconductor physics/chemistry, RF engineering, analogue design,etc. that make modern telecommunications possible has very little to do with the fashion companies who consumers (and unfortunately much of the tech media) associate with it and give the credit (though in this respect Samsung does deserve a bit more credit for their work on NAND flash and displays). The industry simply would not exist TODAY without the overwhelming horizontal integration that already dominates.Yes the efforts of these companies getting cellular communications standardized were immense. And the technology matured. And then they didn't do much with it. It took some youngin's to look at the problem fresh and add the UI that make today's smartphones work. As we have all seen, the moment your technology has matured is the moment you are screwed because someone else now has the opportunity to look at it as a black box and make something new. Each of those manufacturers knew that smartphones would eventually be awesome, but none of them had the UI and software design to make a truly breakout product. Imagine if Motorola would have been smart enough to buy the Android guys instead of Google. Instead, Google bought a bunch of patents on that cellular black box to try to defend it's platform.And when you think about it, which consumes more man years of engineering effort per year at this point.... iterating that cellular black box or developing the OS, services and apps that power today's smartphones?
Intel had better decide that they are competing in this space "for real", or they are screwed. They've already let the Atom languish for five years, during which ARM has completely caught up in performance.Just like Tim Cook said, if you don't cannibalize your own markets someone else will do it for you.Whether Intel will embrace that concept in time remains to be seen. Personally, I hope they don't; if Intel transforms into a chipless Fab company (like TSMC) everyone benefits.
I still think Samsung has the advantage long term because they have both the SOC and the memory products. As mentioned in the article, TSV's (Through Silicon Via's) are going to be quite a disruption. Today, people normally stack an LPDDR2 package on top of their SOC package (POP or Package On Package). Within the LPDDR2 package, you could have a stack of DRAM die typically with wire bonding connecting the die within the package.Once you more to TSV's, you can have a LOT more connections between the SOC and its DRAM's. While this is being standardized through JEDEC (http://www.jedec.org/category/technolog ... a/3d-ics-0), Samsung has all the pieces in house to do whatever they want. You could see a 512 bit or higher bus from the SOC to the memory. The trick is that the memory and the SOC need to line up with each other when you stack them. This gives Samsung an inherent advantage.This isn't just going to impact mobile either. Take a look at that JEDEC link. It also lists High Bandwidth Memory (HBM). This is a 1024 bit bus that provides 128GBytes/s to 256GBytes/s of bandwidth to a stack of up to 8 DRAM's. Here is your processor that includes 8-16 cores and 4GBytes of really, really, fast DRAM... No DIMMs required. How many of them do you want in your server rack?If I was Intel or Apple, I would be thinking seriously about making some investments in Micron to guarantee they make some compelling DRAM's to integrate with their SOC's and processors... otherwise Samsung is going to blow them out of the water on bandwidth.
Great_Scott wrote:Intel had better decide that they are competing in this space "for real", or they are screwed. They've already let the Atom languish for five years, during which ARM has completely caught up in performance.Just like Tim Cook said, if you don't cannibalize your own markets someone else will do it for you.Whether Intel will embrace that concept in time remains to be seen. Personally, I hope they don't; if Intel transforms into a chipless Fab company (like TSMC) everyone benefits.It's true that Atom has stood still for too long, but honestly it's pretty amazing how Atom is still competitive with current ARM chips. The Z2760 is even 32nm vs 28nm of the latest Krait and A15 chips.But that's all changing with Atom moving to the tick tock schedule this year. It wouldn't even surprise me to see Apple move to Intel chips for IOS.And I don't see how Intel moving to a chipless Fab company would help everyone. It certainly wouldn't help Intel.
Mabsark wrote:ggeezz wrote:Intel cannot abandon the phone/tablet market. Desktop/laptop sales are stagnating/decreasing and phones/tablets are on the rise. This trend is only going to increase going forward.But you're right, they're going to have use their fabs that are a step or two behind the cutting the edge. But they're going to have to up their game in the tablet space to even be able to do that.Actually, that trend will not simply keep increasing going forward. The reason desktop/laptop sales are stagnating/decreasing is due to the fact that most people already have one and therefore don't need to buy another one. The exact same thing will happen with tablets as well. Sales are increasing now because people without tablets are buying them. When most people already own a tablet, they won't be buying a new one every year and therefore sales will stagnate/decrease.The PC market is saturated and in a couple of years, the tablet market will be saturated too. Basically, in order to increase sales in a saturated market, you need to increase the population growth or decrease the longevity of the product.Yes and no. I'm not sure the tablet market will saturate in a "couple of years." It may be more like 5 years. But that's a quibble.Here's the real issue. Right now Apple wants you to own an iPhone AND iPad AND Macbook AND iWatch AND Apple TV. Microsoft, OTOH, is making the Surface so that you could ditch your laptop and just use a Surface. Not everyone, but some people.If 5 years from now, we're in a world where a significant number of people use a Surface-type device instead of a laptop, then the PC market is going to contract significantly. Maybe some of the tablet-like devices will use moderately expensive Intel chips, but some of them are going to use cheaper chips.
GravyGraphics wrote:I still think Samsung has the advantage long term because they have both the SOC and the memory products. As mentioned in the article, TSV's (Through Silicon Via's) are going to be quite a disruption. Today, people normally stack an LPDDR2 package on top of their SOC package (POP or Package On Package). Within the LPDDR2 package, you could have a stack of DRAM die typically with wire bonding connecting the die within the package.Once you more to TSV's, you can have a LOT more connections between the SOC and its DRAM's. While this is being standardized through JEDEC (http://www.jedec.org/category/technolog ... a/3d-ics-0), Samsung has all the pieces in house to do whatever they want. You could see a 512 bit or higher bus from the SOC to the memory. The trick is that the memory and the SOC need to line up with each other when you stack them. This gives Samsung an inherent advantage.This isn't just going to impact mobile either. Take a look at that JEDEC link. It also lists High Bandwidth Memory (HBM). This is a 1024 bit bus that provides 128GBytes/s to 256GBytes/s of bandwidth to a stack of up to 8 DRAM's. Here is your processor that includes 8-16 cores and 4GBytes of really, really, fast DRAM... No DIMMs required. How many of them do you want in your server rack?If I was Intel or Apple, I would be thinking seriously about making some investments in Micron to guarantee they make some compelling DRAM's to integrate with their SOC's and processors... otherwise Samsung is going to blow them out of the water on bandwidth.Why not AMD? Last I checked they still made memory...and processors/GPUs.

Answer: Flexibility.


Input: What are the three synthetic types of vitamin K?

Context:
Vitamin K - Wikipedia
(Redirected from Vitamin k)
This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. (November 2015)
This article is about the family of vitamers. For vitamin K1 the form usually used as a supplement, see Phytomenadione.
Vitamin K structures. MK-4 and MK-7 are both subtypes of K2.
Vitamin K deficiency, Warfarin overdose
Vitamin K is a group of structurally similar, fat-soluble vitamins the human body requires for complete synthesis of certain proteins that are prerequisites for blood coagulation and which the body also needs for controlling binding of calcium in bones and other tissues. The vitamin K-related modification of the proteins allows them to bind calcium ions, which they cannot do otherwise. Without vitamin K, blood coagulation is seriously impaired, and uncontrolled bleeding occurs. Low levels of vitamin K also weaken bones and promote calcification of arteries and other soft tissues[citation needed].
Chemically, the vitamin K family comprises 2-methyl-1,4-naphthoquinone (3-) derivatives. Vitamin K includes two natural vitamers: vitamin K1 and vitamin K2.[1] Vitamin K2, in turn, consists of a number of related chemical subtypes, with differing lengths of carbon side chains made of isoprenoid groups of atoms.
Vitamin K1, also known as phylloquinone, is made by plants, and is found in highest amounts in green leafy vegetables because it is directly involved in photosynthesis. It may be thought of as the plant form of vitamin K. It is active as a vitamin in animals and performs the classic functions of vitamin K, including its activity in the production of blood-clotting proteins. Animals may also convert it to vitamin K2.
Bacteria in the gut flora can also convert K1 into vitamin K2. In addition, bacteria typically lengthen the isoprenoid side chain of vitamin K2 to produce a range of vitamin K2 forms, most notably the MK-7 to MK-11 homologues of vitamin K2. All forms of K2 other than MK-4 can only be produced by bacteria, which use these forms in anaerobic respiration. The MK-7 and other bacterially derived forms of vitamin K2 exhibit vitamin K activity in animals, but MK-7's extra utility over MK-4, if any, is unclear and is a matter of investigation.
Three synthetic types of vitamin K are known: vitamins K3, K4, and K5. Although the natural K1 and all K2 homologues and synthetic K4 and K5 have proven nontoxic, the synthetic form K3 (menadione) has shown toxicity.[2]
1.2 Cardiovascular health
1.4 Coumarin poisoning
4.1 Conversion of vitamin K1 to vitamin K2
4.2 Vitamin K2
6 Absorption and dietary need
7 Dietary reference intake
10 Biochemistry
10.1 Function in animals
10.2 Gamma-carboxyglutamate proteins
10.3 Methods of assessment
10.4 Function in bacteria
11 Injection in newborns
11.3 Controversy
A review of 2014 concluded that there is positive evidence that monotherapy using MK-4, one of the forms of Vitamin K2, reduces fracture incidence in post-menopausal women with osteoporosis, and suggested further research on the combined use of MK-4 with bisphosphonates. In contrast, an earlier review article of 2013 concluded that there is no good evidence that vitamin K supplementation helps prevent osteoporosis or fractures in postmenopausal women.[3]
A Cochrane systematic review of 2006 suggested that supplementation with Vitamin K1 and with MK4 reduces bone loss; in particular, a strong effect of MK-4 on incident fractures among Japanese patients was emphasized.[4]
A review article of 2016 suggested to consider, as one of several measures for bone health, increasing the intake of foods rich in vitamins K1 and K2.[5]
Cardiovascular health[edit]
Adequate intake of vitamin K is associated with the inhibition of arterial calcification and stiffening,[6] but there have been few interventional studies and no good evidence that vitamin K supplementation is of any benefit in the primary prevention of cardiovascular disease.[7]
One 10-year population study, the Rotterdam Study, did show a clear and significant inverse relationship between the highest intake levels of menaquinone (mainly MK-4 from eggs and meat, and MK-8 and MK-9 from cheese) and cardiovascular disease and all-cause mortality in older men and women.[8]
Vitamin K has been promoted in supplement form with claims it can slow tumor growth; there is however no good medical evidence that supports such claims.[9]
Coumarin poisoning[edit]
Vitamin K is part of the suggested treatment regime for poisoning by rodenticide (coumarin poisoning).[10]
Although allergic reaction from supplementation is possible, no known toxicity is associated with high doses of the phylloquinone (vitamin K1) or menaquinone (vitamin K2) forms of vitamin K, so no tolerable upper intake level (UL) has been set.[11]
Blood clotting (coagulation) studies in humans using 45 mg per day of vitamin K2 (as MK-4)[12] and even up to 135 mg per day (45 mg three times daily) of K2 (as MK-4),[13] showed no increase in blood clot risk. Even doses in rats as high as 250 mg/kg, body weight did not alter the tendency for blood-clot formation to occur.[14]
Unlike the safe natural forms of vitamin K1 and vitamin K2 and their various isomers, a synthetic form of vitamin K, vitamin K3 (menadione), is demonstrably toxic at high levels. The U.S. FDA has banned this form from over-the-counter sale in the United States because large doses have been shown to cause allergic reactions, hemolytic anemia, and cytotoxicity in liver cells.[2]
Phylloquinone (K1)[15][16] or menaquinone (K2) are capable of reversing the anticoagulant activity of the anticoagulant warfarin (tradename Coumadin). Warfarin works by blocking recycling of vitamin K, so that the body and tissues have lower levels of active vitamin K, and thus a deficiency of vitamin K.
Supplemental vitamin K (for which oral dosing is often more active than injectable dosing in human adults) reverses the vitamin K deficiency caused by warfarin, and therefore reduces the intended anticoagulant action of warfarin and related drugs.[17] Sometimes small amounts of vitamin K are given orally to patients taking warfarin so that the action of the drug is more predictable.[17] The proper anticoagulant action of the drug is a function of vitamin K intake and drug dose, and due to differing absorption must be individualized for each patient.[citation needed] The action of warfarin and vitamin K both require two to five days after dosing to have maximum effect, and neither warfarin or vitamin K shows much effect in the first 24 hours after they are given.[18]
The newer anticoagulants dabigatran and rivaroxaban have different mechanisms of action that do not interact with vitamin K, and may be taken with supplemental vitamin K.[19][20]
Vitamin K2 (menaquinone). In menaquinone, the side chain is composed of a varying number of isoprenoid residues. The most common number of these residues is four, since animal enzymes normally produce menaquinone-4 from plant phylloquinone.
A sample of phytomenadione for injection, also called phylloquinone
The three synthetic forms of vitamin K are vitamins K3 (menadione), K4, and K5, which are used in many areas, including the pet food industry (vitamin K3) and to inhibit fungal growth (vitamin K5).[21]
Conversion of vitamin K1 to vitamin K2[edit]
Vitamin K1 (phylloquinone) – both forms of the vitamin contain a functional naphthoquinone ring and an aliphatic side chain. Phylloquinone has a phytyl side chain.
The MK-4 form of vitamin K2 is produced by conversion of vitamin K1 in the testes, pancreas, and arterial walls.[22] While major questions still surround the biochemical pathway for this transformation, the conversion is not dependent on gut bacteria, as it occurs in germ-free rats[23][24] and in parenterally-administered K1 in rats.[25][26] In fact, tissues that accumulate high amounts of MK-4 have a remarkable capacity to convert up to 90% of the available K1 into MK-4.[27][28] There is evidence that the conversion proceeds by removal of the phytyl tail of K1 to produce menadione as an intermediate, which is then condensed with an activated geranylgeranyl moiety (see also prenylation) to produce vitamin K2 in the MK-4 (menatetrione) form.[29]
Vitamin K2[edit]
Main article: Vitamin K2
Vitamin K2 (menaquinone) includes several subtypes. The two subtypes most studied are menaquinone-4 (menatetrenone, MK-4) and menaquinone-7 (MK-7).
Vitamin K1, the precursor of most vitamin K in nature, is a stereoisomer of phylloquinone, an important chemical in green plants, where it functions as an electron acceptor in photosystem I during photosynthesis. For this reason, vitamin K1 is found in large quantities in the photosynthetic tissues of plants (green leaves, and dark green leafy vegetables such as romaine lettuce, kale and spinach), but it occurs in far smaller quantities in other plant tissues (roots, fruits, etc.). Iceberg lettuce contains relatively little. The function of phylloquinone in plants appears to have no resemblance to its later metabolic and biochemical function (as "vitamin K") in animals, where it performs a completely different biochemical reaction.
Vitamin K (in animals) is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate (Gla) residues. The modified residues are often (but not always) situated within specific protein domains called Gla domains. Gla residues are usually involved in binding calcium, and are essential for the biological activity of all known Gla proteins.[30]
At this time[update], 17 human proteins with Gla domains have been discovered, and they play key roles in the regulation of three physiological processes:
Blood coagulation: prothrombin (factor II), factors VII, IX, and X, and proteins C, S, and Z[31]
Bone metabolism: osteocalcin, also called bone Gla protein (BGP), matrix Gla protein (MGP),[32] periostin,[33] and the recently discovered Gla-rich protein (GRP).[34][35]
Vascular biology: growth arrest-specific protein 6 (Gas6)[36]
Unknown function: proline-rich γ-carboxyglutamyl proteins (PRGPs) 1 and 2, and transmembrane γ-carboxy glutamyl proteins (TMGs) 3 and 4.[37]
Like other lipid-soluble vitamins (A, D and E), vitamin K is stored in the fatty tissue of the human body.
Absorption and dietary need[edit]
Previous theory held that dietary deficiency is extremely rare unless the small intestine was heavily damaged, resulting in malabsorption of the molecule. Another at-risk group for deficiency were those subject to decreased production of K2 by normal intestinal microbiota, as seen in broad spectrum antibiotic use.[38] Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared with those not taking these antibiotics.[39] Diets low in vitamin K also decrease the body's vitamin K concentration.[40] Those with chronic kidney disease are at risk for vitamin K deficiency, as well as vitamin D deficiency, and particularly those with the apoE4 genotype.[41] Additionally, in the elderly there is a reduction in vitamin K2 production.[42]
The National Academy of Medicine (NAM) updated an estimate of what constitutes an adequate intake (AI) for vitamin K in 2001. The NAM does not distinguish between K1 and K2 – both are counted as vitamin K. At that time there was not sufficient evidence to set the more rigorous estimated average requirement (EAR) or recommended dietary allowance (RDA) given for most of the essential vitamins and minerals. The current daily AIs for vitamin K for adult women and men are 90 μg and 120 μg respectively. The AI for pregnancy and lactation is 90 μg. For infants up to 12 months the AI is 2–2.5 μg, and for children aged 1 to 18 years the AI increases with age from 30 to 75 μg. As for safety, the FNB also sets tolerable upper intake levels (known as ULs) for vitamins and minerals when evidence is sufficient. In the case of vitamin K no UL is set, as evidence for adverse effects is not sufficient. Collectively EARs, RDAs, AIs and ULs are referred to as dietary reference intakes.[43] The European Food Safety Authority reviewed the same safety question and did not set an UL.[44]
For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percentage of daily value (%DV). For vitamin K labeling purposes the daily value was 80 μg, but as of May 2016 it has been revised upwards to 120 μg. A table of the pre-change adult daily values is provided at reference daily intake. Food and supplement companies have until 28 July 2018 to comply with the change.
See also: Vitamin K2 § Dietary sources
K1 (μg)[45]
Kale, cooked
Collards, cooked
Collards, raw
Swiss chard, cooked
Swiss chard, raw
Turnip greens, raw
Romaine lettuce, raw
Table from "Important information to know when you are taking: Warfarin (Coumadin) and Vitamin K", Clinical Center, National Institutes of Health Drug Nutrient Interaction Task Force.[46]
Vitamin K1 is found chiefly in leafy green vegetables such as dandelion greens (which contain 778.4 μg per 100 g, or 741% of the recommended daily amount), spinach, swiss chard, lettuce and Brassica vegetables (such as cabbage, kale, cauliflower, broccoli, and brussels sprouts) and often the absorption is greater when accompanied by fats such as butter or oils; some fruits, such as avocados, kiwifruit and grapes, are also high in vitamin K. By way of reference, two tablespoons of parsley contains 153% of the recommended daily amount of vitamin K.[47] Some vegetable oils, notably soybean oil, contain vitamin K, but at levels that would require relatively large calorie consumption to meet the USDA-recommended levels.[48] colonic bacteria synthesize a significant portion of humans' vitamin K needs; newborns often receive a vitamin K shot at birth to tide them over until their colons become colonized at five to seven days of age from the consumption of breast milk.
The tight binding of vitamin K1 to thylakoid membranes in chloroplasts makes it less bioavailable. For example, cooked spinach has a 5% bioavailability of phylloquinone, however, fat added to it increases bioavailability to 13% due to the increased solubility of vitamin K in fat.[49]
Main article: Vitamin K deficiency
Average diets are usually not lacking in vitamin K, and primary deficiency is rare in healthy adults. Newborn infants are at an increased risk of deficiency. Other populations with an increased prevalence of vitamin K deficiency include those who suffer from liver damage or disease (e.g. alcoholics), cystic fibrosis, or inflammatory bowel diseases, or have recently had abdominal surgeries. Secondary vitamin K deficiency can occur in people with bulimia, those on stringent diets, and those taking anticoagulants. Other drugs associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanisms are still unknown. Vitamin K1 deficiency can result in coagulopathy, a bleeding disorder.[50]Symptoms of K1 deficiency include anemia, bruising, nosebleeds and bleeding of the gums in both sexes, and heavy menstrual bleeding in women.
Osteoporosis[51][52] and coronary heart disease[53][54] are strongly associated with lower levels of K2 (menaquinone). Vitamin K2 (as menaquinones MK-4 through MK-10) intake level is inversely related to severe aortic calcification and all-cause mortality.[8]
Function in animals[edit]
Mechanism of action of vitamin K1.
The function of vitamin K2 in the animal cell is to add a carboxylic acid functional group to a glutamate (Glu) amino acid residue in a protein, to form a gamma-carboxyglutamate (Gla) residue. This is a somewhat uncommon posttranslational modification of the protein, which is then known as a "Gla protein". The presence of two −COOH (carboxylic acid) groups on the same carbon in the gamma-carboxyglutamate residue allows it to chelate calcium ions. The binding of calcium ions in this way very often triggers the function or binding of Gla-protein enzymes, such as the so-called vitamin K-dependent clotting factors discussed below.
Within the cell, vitamin K undergoes electron reduction to a reduced form called vitamin K hydroquinone, catalyzed by the enzyme vitamin K epoxide reductase (VKOR).[55] Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called gamma-glutamyl carboxylase[56][57] or the vitamin K-dependent carboxylase. The carboxylation reaction only proceeds if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time. The carboxylation and epoxidation reactions are said to be coupled. Vitamin K epoxide is then reconverted to vitamin K by VKOR. The reduction and subsequent reoxidation of vitamin K coupled with carboxylation of Glu is called the vitamin K cycle.[58] Humans are rarely deficient in vitamin K1 because, in part, vitamin K1 is continuously recycled in cells.[59]
Warfarin and other 4-hydroxycoumarins block the action of VKOR.[60] This results in decreased concentrations of vitamin K and vitamin K hydroquinone in tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient. This results in the production of clotting factors with inadequate Gla. Without Gla on the amino termini of these factors, they no longer bind stably to the blood vessel endothelium and cannot activate clotting to allow formation of a clot during tissue injury. As it is impossible to predict what dose of warfarin will give the desired degree of clotting suppression, warfarin treatment must be carefully monitored to avoid overdose.
Gamma-carboxyglutamate proteins[edit]
Main article: Gla domain
The following human Gla-containing proteins ("Gla proteins") have been characterized to the level of primary structure: blood coagulation factors II (prothrombin), VII, IX, and X, anticoagulant proteins C and S, and the factor X-targeting protein Z. The bone Gla protein osteocalcin, the calcification-inhibiting matrix Gla protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs), the function of which is at present unknown. Gas6 can function as a growth factor to activate the Axl receptor tyrosine kinase and stimulate cell proliferation or prevent apoptosis in some cells. In all cases in which their function was known, the presence of the Gla residues in these proteins turned out to be essential for functional activity.
Gla proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom of a number of Australian snakes acts by activating the human blood-clotting system. In some cases, activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.
Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus.[61] These snails produce a venom containing hundreds of neuroactive peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain two to five Gla residues.[62]
Methods of assessment[edit]
Vitamin K status can be assessed by:
The prothrombin time (PT) test measures the time required for blood to clot. A blood sample is mixed with citric acid and put in a fibrometer; delayed clot formation indicates a deficiency. This test is insensitive to mild deficiency, as the values do not change until the concentration of prothrombin in the blood has declined by at least 50%.[63]
Undercarboxylated prothrombin (PIVKA-II); in a study of 53 newborns, found "PT (prothrombin time) is a less sensitive marker than PIVKA II",[64] and as indicated above, PT is unable to detect subclinical deficiencies that can be detected with PIVKA-II testing.
Plasma phylloquinone was found to be positively correlated with phylloquinone intake in elderly British women, but not men,[65] but an article by Schurgers et al. reported no correlation between FFQ[further explanation needed] and plasma phylloquinone.[66]
Urinary γ-carboxyglutamic acid responds to changes in dietary vitamin K intake. Several days are required before any change can be observed. In a study by Booth et al., increases of phylloquinone intakes from 100 μg to between 377 and 417 μg for five days did not induce a significant change. Response may be age-specific.[67]
Undercarboxylated osteocalcin (UcOc) levels have been inversely correlated with stores of vitamin K[68] and bone strength in developing rat tibiae. Another study following 78 post-menopausal Korean women found a supplement regimen of vitamins K and D, and calcium, but not a regimen of vitamin D and calcium, was inversely correlated with reduced UcOc levels.[69]
Function in bacteria[edit]
Many bacteria, such as Escherichia coli found in the large intestine, can synthesize vitamin K2 (menaquinone-7 or MK-7, up to MK-11),[70] but not vitamin K1 (phylloquinone). In these bacteria, menaquinone transfers two electrons between two different small molecules, during oxygen-independent metabolic energy production processes (anaerobic respiration).[71] For example, a small molecule with an excess of electrons (also called an electron donor) such as lactate, formate, or NADH, with the help of an enzyme, passes two electrons to menaquinone. The menaquinone, with the help of another enzyme, then transfers these two electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor). Adding two electrons to fumarate or nitrate converts the molecule to succinate or nitrite plus water, respectively.
Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except the final electron acceptor is not molecular oxygen, but fumarate or nitrate. In aerobic respiration, the final oxidant is molecular oxygen (O2), which accepts four electrons from an electron donor such as NADH to be converted to water. E. coli, as facultative anaerobes, can carry out both aerobic respiration and menaquinone-mediated anaerobic respiration.
Injection in newborns[edit]
The blood clotting factors of newborn babies are roughly 30–60% that of adult values; this may be due to the reduced synthesis of precursor proteins and the sterility of their guts. Human milk contains 1–4 μg/L of vitamin K1, while formula-derived milk can contain up to 100 μg/L in supplemented formulas. Vitamin K2 concentrations in human milk appear to be much lower than those of vitamin K1. Occurrence of vitamin K deficiency bleeding in the first week of the infant's life is estimated at 0.25–1.7%, with a prevalence of 2–10 cases per 100,000 births.[72] Premature babies have even lower levels of the vitamin, so they are at a higher risk from this deficiency.
Bleeding in infants due to vitamin K deficiency can be severe, leading to hospitalization, blood transfusions, brain damage, and death. Supplementation can prevent most cases of vitamin K deficiency bleeding in the newborn. Intramuscular administration is more effective in preventing late vitamin K deficiency bleeding than oral administration.[73][74]
As a result of the occurrences of vitamin K deficiency bleeding, the Committee on Nutrition of the American Academy of Pediatrics has recommended 0.5–1 mg of vitamin K1 be administered to all newborns shortly after birth.[74]
In the UK vitamin K supplementation is recommended for all newborns within the first 24 hours.[75] This is usually given as a single intramuscular injection of 1 mg shortly after birth but as a second-line option can be given by three oral doses over the first month.[76]
Controversy arose in the early 1990s regarding this practice, when two studies suggested a relationship between parenteral administration of vitamin K and childhood cancer,[77] however, poor methods and small sample sizes led to the discrediting of these studies, and a review of the evidence published in 2000 by Ross and Davies found no link between the two.[78] Doctors reported emerging concerns in 2013,[79] after treating children for serious bleeding problems. They cited lack-of newborn vitamin K administration, as the reason that the problems occurred, and recommended that breastfed babies could have an increased risk unless they receive a preventative dose.
In the early 1930s, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet.[80] He initially replicated experiments reported by scientists at the Ontario Agricultural College (OAC).[81] McFarlane, Graham and Richardson, working on the chick feed program at OAC, had used chloroform to remove all fat from chick chow. They noticed that chicks fed only fat-depleted chow developed hemorrhages and started bleeding from tag sites.[82] Dam found that these defects could not be restored by adding purified cholesterol to the diet. It appeared that – together with the cholesterol – a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin. Edward Adelbert Doisy of Saint Louis University did much of the research that led to the discovery of the structure and chemical nature of vitamin K.[83] Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on vitamin K (K1 and K2) published in 1939. Several laboratories synthesized the compound(s) in 1939.[84]
For several decades, the vitamin K-deficient chick model was the only method of quantifying vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content. Three groups of physicians independently found this: Biochemical Institute, University of Copenhagen (Dam and Johannes Glavind), University of Iowa Department of Pathology (Emory Warner, Kenneth Brinkhous, and Harry Pratt Smith), and the Mayo Clinic (Hugh Butt, Albert Snell, and Arnold Osterberg).[85]
The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 by Smith, Warner, and Brinkhous.[86]
The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al.,[87] Nelsestuen et al.,[88] and Magnusson et al.[89]) isolated the vitamin K-dependent coagulation factor prothrombin (factor II) from cows that received a high dose of a vitamin K antagonist, warfarin. It was shown that, while warfarin-treated cows had a form of prothrombin that contained 10 glutamate (Glu) amino acid residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues that were chemically identified as γ-carboxyglutamate (Gla). The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.
The biochemistry of how vitamin K is used to convert Glu to Gla has been elucidated over the past thirty years in academic laboratories throughout the world.
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Identification of gamma-carboxyglutamic acid as a component of prothrombin" (PDF). Journal of Biological Chemistry. 249 (19): 6347–6350. PMID 4214105. ^ Magnusson, S.; Sottrup-Jensen, L.; Petersen, T. E.; Morris, H. R.; Dell, A. (Aug 1974). "Primary structure of the vitamin K-dependent part of prothrombin". FEBS Letters. 44 (2): 189–193. doi:10.1016/0014-5793(74)80723-4. PMID 4472513. Bibliography[edit]
Rhéaume-Bleue, Kate (2012). Vitamin K2 and the Calcium Paradox. John Wiley & Sons, Canada. ISBN 1-118-06572-7. External links[edit]
"Vitamin K: Another Reason to Eat Your Greens". v
TPP / ThDP (B1)
FMN, FAD (B2)
NAD+, NADH, NADP+, NADPH (B3)
Coenzyme A (B5)
PLP / P5P (B6)
THFA / H4FA, DHFA / H2FA, MTHF (B9)
AdoCbl, MeCbl (B12)
Phylloquinone (K1), Menaquinone (K2)
non-vitamins
Coenzyme B
Heme / Haem (A, B, C, O)
Molybdopterin/Molybdenum cofactor
THMPT / H4MPT
Fe2+, Fe3+
vitamins: see vitamins
Antihemorrhagics (B02)
(coagulation)
Phytomenadione (K1)
Menadione (K3)
intrinsic: IX/Nonacog alfa
VIII/Moroctocog alfa/Turoctocog alfa
extrinsic: VII/Eptacog alfa
common: X
II/Thrombin
I/Fibrinogen
XIII/Catridecacog
combinations: Prothrombin complex concentrate (II, VII, IX, X, protein C and S)
Carbazochrome
thrombopoietin receptor agonist (Romiplostim
Eltrombopag)
Tetragalacturonic acid hydroxymethylester
Epinephrine/Adrenalone
amino acids (Aminocaproic acid
Aminomethylbenzoic acid)
serpins (Aprotinin
Alfa1 antitrypsin
Camostat).

Answer: Vitamins K3, K4, and K5.