page_title: Smith–Lemli–Opitz syndrome
section_title: Metabolism
hierarchical_section_title: Smith–Lemli–Opitz syndrome / Cholesterol metabolism and function / Metabolism
caption_attribution_description: English: Mevalonate pathway.
context_page_description: Smith–Lemli–Opitz syndrome is an inborn error of cholesterol synthesis. It is an autosomal recessive, multiple malformation syndrome caused by a mutation in the enzyme 7-Dehydrocholesterol reductase encoded by the DHCR7 gene. It causes a broad spectrum of effects, ranging from mild intellectual disability and behavioural problems to lethal malformations.
context_section_description: Cholesterol can be obtained through the diet, but it can also be formed by metabolism in the body. Cholesterol metabolism primarily takes place in the liver, with significant amounts in the intestine as well. It should also be noted that cholesterol cannot pass the blood–brain barrier, thus within the brain, biosynthesis is the only source of cholesterol.
  In humans, cholesterol synthesis begins with the mevalonate pathway (see diagram), leading to the synthesis of farnesyl pyrophosphate (FPP). This pathway uses two acetyl-CoA and two NADPH to make mevalonate, which is metabolized to isopentenyl pyrophosphate (IPP) using three ATP. From there, three IPP are needed to make one FPP. The combination of two FPP leads to the formation of squalene; this represents the first committed step towards cholesterol biosynthesis. Squalene leads to the creation of lanosterol, from which there are multiple pathways that lead to cholesterol biosynthesis. The rate limiting step of cholesterol synthesis is the conversion of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonate, this is an early step in the mevalonate pathway catalyzed by HMG-CoA reductase.
  Through a complicated series of reactions, lanosterol leads to the formation of zymosterol. As shown in a diagram to the right, it is at this point that the pathway diverges. In humans, the main pathway leading to cholesterol is known as the Kandutsch–Russell pathway. Zymosterol is metabolized to 5α-cholesta-7,24-dien-3β-ol, then to lathosterol, and then to 7-dehydrocholesterol, or 7-DHC. 7-DHC is the immediate precursor to cholesterol, and the enzyme DHCR7 is responsible for converting 7-DHC to cholesterol. DHCR7 reduces the double bond on carbon 7 of 7-DHC, leading to the unesterified product. Mutations in this enzyme are responsible for the wide range of defects present in SLOS. In another pathway leading to cholesterol synthesis, DHCR7 is required for the reduction of 7-Dehydrodesmosterol to desmosterol.
caption: Mevalonate pathway.
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