Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : July 22, 2022
Accepted : August 14, 2022
Published online : September 30, 2022
doi:10.24659/gsr.9.3_129

Review article

Generation of short chain aldehydes and glyceraldehyde 3-phosphate
dehydrogenase (GAPDH)
Kenji Sato 1), Yifeng Zheng 1), Agustin Martin-Morales 1), Toshio Taira 2), Yoshikazu Yonei 3)1) Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan2) Sapporo Division, Cosmo Bio Co., Ltd., Otaru, Hokkaido, Japan3) Anti-Aging Medical Research Center/Glycative Stress Research Center,
Graduate School of Life and Medical Sciences, Doshisha University, Kyoto, Japan

Abstract

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is an enzyme involved in the glycolytic pathway. From the substratesof GAPDH, toxic aldehydes, such as glyceraldehyde and methylglyoxal, can be generated. Inhibition of GAPDH in HCT116
cells by koningin acid increased glyceraldehyde. Animal experiments demonstrated that high fat diet-feeding significantly
decreased mice liver GAPDH in protein level with increase of lipid peroxidation, liver damage, and shortage of liver cysteine.
On the other hand, some food compounds, a water extract of chlorella and its constituent (phenethylamine), ameliorated
high fat diet-induced decrease of GAPDH and following pathological events. Treatment with these compounds significantly
decreased liver methylglyoxal. Cysteine can react with short chain glyceraldehydes including methylglyoxal and convert themto nontoxic metabolites. These facts indicate that decrease of GAPDH can increase toxic aldehydes in liver and induce liver
damage and some food compounds can ameliorate liver damage via recovering GAPDH.

KEY WORDS: glyceraldehyde 3-phosphate dehydrogenase (GAPDH), glyceraldehyde, methylglyoxal,		short-chain aldehydes, high fat diet

1. Background.
Most organisms have a glycolytic system thatmetabolizes glucose to pyruvate. The glycolytic system canproduce ATP without the need for oxygen. In glycolysis,
glyceraldehyde 3 -phosphate, an intermediate product,is oxidized by the coenzyme, nicotinamide adenine
dinucleotide (NAD + ), and concurrently bound with a
new phosphate, resulting in 1, 3 - diphosphoglycerate,from which the phosphate group at position 1 is thenreleased to yield 3-phosphoglyceric acid. Conjugated tothis reaction, two molecules of ATP are synthesized permolecule of glucose. The enzyme catalyzing the formationof 1, 3- diphosphoglycerate is glyceraldehyde 3 -phosphate
dehydrogenase (GAPDH). GAPDH has traditionally been
considered a housekeeping gene product and used as aninternal standard in Western blot and qPCR analyses.
However, GAPDH has been found to have moon-lightfunctions other than being a glycolytic enzyme, such as

inducing apoptosis 1). It has also been reported that theexpression of GAPDH in the liver fluctuates with a high fat
diet (HFD) 2, 3). Therefore, the use of GAPDH as an internal
standard has been questioned.
If GAPDH as a glycolytic enzyme decreases,
glyceraldehyde 3-phosphate and its isomer dihydroxyacetone
phosphate, which are substrates of GAPDH, would
accumulate without being metabolized. It is known
that short-chain aldehydes (SCAs), i.e., highly reactive
glyceraldehyde (GA) and methylglyoxal (MGO), are formed
from glyceraldehyde 3 - phosphate and dihydroxyacetone
phosphate 4). These SCAs are thought to react with amino andthiol groups of proteins, thereby reducing protein function 5).
The reactants (advanced glycation endproducts: AGEs)
bind to receptors (RAGE) in vascular endothelial cells andimmune-response cells, and induce inflammatory responses,
so-called glycative stress 6). Therefore, a decrease in GAPDH
in the glycolytic system or a decrease in its activity may
cause glycative stress. However, the relationship between

Corresponding to: Professor Keji Sato PhD
Division of Applied Biosciences, Graduate School of Agriculture,
Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan
TEL : +81-75-753-6444 e-mail: sato.kenji.7x@kyoto-u.ac.jp
Co-authors; Zheng Y, zhengyifeng1989@yeah.net;
Martin-Morales A, agusmartinmorales@gmail.com;
Taira T. tairatoshio@rohto.co.jp; Yonei Y, yyonei@mail.doshisha.ac.jp

Glycative Stress Research 2022; 9 (3) : 129-134(c) Society for Glycative Stress Research_ 12 9 _short Chain Aldehydes and GAPDHGAPDH and SCAs has not received much attention, as only
an inverse correlation between GAPDH activity and MGO
production has been reported in erythrocytes 7). This reportpresents recent in vitro and in vivo findings on the relation
between GAPDH and the formation of SCAs.

2. Glyceraldehyde and methylglyoxal
content in vivo
MGO, a dicarbonyl compound, has been
determined with high sensitivity by derivatization with
2, 3-diaminonaphthalene (DAN) 8). MGO has been shown
to be present in the liver in amounts of several tens ofµmol/kg, but in plasma it is present at the detection limit(low µmol/L). It has also been shown that plasma MGO is
increased in diabetic patients 4, 9). In contrast, highly sensitive
determination of GA, a monocarbonyl compound, has beendifficult. Recently, a stable and sensitive determination of
GA in biological sample became possible by optimizing
the conditions for 1-phenyl-3-methyl-5-pyrazolone (PMP)
derivatization 10). Using this technique, GA in plasma of
healthy subjects and type 2 diabetics has been reported. The
content varies 2 - 20 μM and a strong correlation with blood
glucose has been reported in type 2 diabetes patients 10).
Compared to blood glucose (about 100 mg/dL), the plasma
GA is naturally much lower. However, most glucose has ahemiacetal structure, and the linear aldehyde form in solution(0.001% - 0.003% of total glucose) 11) is considerably lessthan GA 10). Therefore, glycative stress on blood vessels
is higher for GA, one of SCAs, than for blood glucose.
Previously, immunostaining has shown that GA-derived AGEs
are increased in animal models and patients with diabetes.
Based on these findings, it has also been proposed that thisAGE derived from GA is called toxic AGE (TAGE) 12, 13).
The aforementioned result that plasma GA is higher thanaldehyde-type glucose in the diabetic patients strongly
supports the above hypothesis that SCAs play an importantrole in glycative stress.

3. In vitro GAPDH activity and short-chain
aldehyde formation
As mentioned above, an inverse correlation has beenshown between GAPDH activity and the generation of MGO
derived from GAPDH substrates in erythrocytes 7). In vitro
experiments using HCT116 cells derived from human colon
adenocarcinoma cells also investigated the relation between
GAPDH activity and formation of GA. When koningin acid(KA), an inhibitor of GAPDH, was added to the medium of
HCT116 cells up to 100 µM the intracellular concentration of
GA increased up to 20 µM KA as shown in Fig. 1-a, b. GA
release to the extracellular space was also observed with theaddition of KA. Intracellular GA was rather reduced at KA
concentrations above 20 μM, while, as shown in Fig. 1-d, e,
HCT116 cells floated up at these concentrations, suggestingthat cell death reduced GA production. Therefore, in vitro
experiments have shown that inhibition of GAPDH produces
MGO or GA.

4. Formation of short-chain
glyceraldehyde by diet.
Since it is now possible to measure GA content in body,the formation of GA and other SCAs by feeding has been
investigated. In healthy subjects, no significant changes inplasma GA were observed after consumption of 100 g ofrice 10). In mice and rats, GA in liver (about 80 - 90 µmol/kg)
has been shown to be higher than in plasma (about 8 - 9 µM).
Overnight fasting significantly decreased GA in the liver,while no significant difference in plasma was found 10). This
result is consistent with the aforementioned human study inwhich plasma GA did not change significantly after meal
ingestion. When mice (CB57/ b6) were fed a long- term (8weeks) HFD (60 % on a caloric basis), GA in the liver was
not significantly different from that in the normal diet group,
however unexpectedly, plasma GA was significantly increased( Fig. 2-a, b). This rearing condition induced liver damage
and caused a significant increase in plasma aspartate
aminotransferase (AST) and alanine aminotransferase(ALT) ( Fig. 2-c, d ) 10). These results indicate that althougha considerable amount of GA is produced in hepatocytes
through metabolism of diet-derived components, its release
into the blood is suppressed under physiological conditions.
However, it can be assumed that GA is leaked fromhepatocytes in the event of hepatic dysfunction 10). Thishypothesis is appealing because it could explain thephenomenon of hepatic dysfunction being associated with theprogression of diabetes mellitus. Later, it will be necessary
to prove this hypothesis using stable isotope tracers.
As mentioned above, sustained HFD feeding to CB57/b6
mice results in liver dysfunction. During this process,antioxidant enzymes in the liver, superoxide dismutase (SOD)
and glutathione peroxidase (GPX) activity were significantly
decreased (Fig. 3-a, b) 14). To examine the expression of both
enzymes at the protein level, Western blot analysis was used.
The analysis, which initially used GAPDH as an internal
standard, showed no significant differences in the protein
content of SOD and GPX, however GAPDH in the mouse
liver was significantly reduced by HFD ( Fig. 3-c, d, e).
Therefore, we examined the GA and NGO contents in theliver and found that long-term HFD did not significantly
alter GA (Fig. 2-a) or MGO in the liver (Fig. 4-a). This may
be partly due to the higher proportion of carbohydrates in thenormal diet compared to HFD. As shown in the next section,a functional food and its ingredient restores the GAPDH anddecreases MGO in the liver of mice fed a high fat diet 14).
These facts indicate that, decrease of GAPDH in liver undersame carbohydrate loading condition can increase of MGO.
MGO is also known to produce oxidative stress 15, 16).
When malondialdehyde, an oxidized product of linoleic acidin the liver, was quantified as 2-thiobarbituric acid reactive
substances (TBARS), TBARS was significantly increased by
HFD (Fig. 4-b) 14). Therefore, it is possible that MGO may
further promote the formation of other SCAs as GAPDH
is reduced by HFD. The reason for the increased formationof MGO over GA in the liver due to decreased GAPDH is
unknown. Next, whether MGO is produced via GA needs tobe examined.
Short-chain aldehydes (SCAs), i.e., MGO, areenzymatically metabolized and detoxified, and are also
known to react with cysteine to form stable thiazoline_ 13 0 _Glycative Stress Researchb)

In cell
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Fig. 1. Effect of KA on HCT116 cell intracellular and medium GA.

HCT116 cells (1 × 10 5 ) were inoculated on 24 well plate and incubated in a high glucose DMEM medium containing 10 % fetal bovine serum.
KA was added to the medium containing one day after inoculation. Cells were harvested 7 days after inoculation and washed with the medium.
Intracellular GA was extracted with 75% ethanol. The intracellular ( a ) and medium ( b ) GA was quantified by the method of Martin-Morales
et al. (Reference 10). Cells after 6 - day incubation with KA ( c : 0 µM, d : 20 µM, and e : 100 µM ) were photographed (lower). Non-publisheddata. KA, koningin acid; GA, glyceraldehyde.

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Liver ( a ) and blood plasma ( b ) GA contents in mice fed control diet and HFD (60 % in calorie) for 8 weeks with plasma AST ( c ) and ALT (d ).
The figure was adapted with permission from Martin-Morales et al. (Reference 10). HFD, high fat diet; GA, glyceraldehyde; AST, aspartate
aminotransferase; ALT, alanine aminotransferase.

_ 131 _

short Chain Aldehydes and GAPDH

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Liver SOD (a ) and GPX (b ) activities and their protein levels (c, d ) with protein levels of GAPDH ( e ) in mice fed ND, HFD, HFD with 100
mg/kg body weight of WEC, and HFD with 10 µg/kg body weight of PHA for 12 weeks. The figure was adapted with permission from Zheng
et al. (Reference 14). SOD, superoxide dismutase; GPX, glutathione peroxidase; HFD, high fat diet; ND, normal diet; WEC, hot water extractof chlorella; PHA, phenethylamine; GAPDH, glyceraldehyde 3-phosphate dehydrogenase.

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Fig. 4. Effects of WEC and PHA on liver dysfunction in HFD feeding mice: Changes of MGO, TBARS and cysteine.

Liver MGO ( a ), TBARS ( b ), and cysteine ( c ) levels in mice fed ND, HFD, HFD with 100 mg/kg body weight of WEC, and HFD with 10µg/kg body weight of PHA for 12 weeks. The figure was adapted with permission from Zheng et al. (Reference 14). MGO, methylglyoxal;
TBARS, malondialdehyde; HFD, high fat diet; ND, normal diet; WEC, hot water extract of chlorella; PHA, phenethylamine.

_ 132 _Glycative Stress Researchcompounds 17). This reaction is considered to be one of thedetoxification actions of SCAs. Therefore, the cysteine
content in liver was determined by labeling the thiol andamino groups with 4-vinylpyridine and 6-amino quinolylN-hydroxysuccinimidyl carbamate (AccQ), respectively.
The results showed that cysteine in the liver was drasticallyreduced to about 1/10 in HFD ( Fig. 4-c) 14). These findings
suggest that MGO and malondialdehyde produced bydecreased GAPDH deplete the cysteine necessary for
detoxification, resulting in the inability to detoxify SCAs,
which in turn causes decreased liver function.

oxidative stress in the liver was improved and liver function
was preserved. Interestingly, administration of WEC and
PHA restored GAPDH, which had been depleted by HFD(Fig. 3-e), resulting in a decrease in MGO in the liver(Fig. 4-a). Furthermore, the depletion of cysteine, which
reacts with SCAs, was significantly improved (Fig. 4-c) 14).
These results support the hypothesis, discussed in theprevious section, that a decrease in GAPDH leads to the
SCA formation, resulting in liver dysfunction. They also
indicate that food components can protect liver function by
suppressing the GAPDH decrease.

5. Inhibition of short-chain aldehyde
formation by food ingredients

6. Future issues

Hot water extract of chlorella is known to improve lipid
metabolism 18). Hot water extract of chlorella has also beenfound to prolong the survival period of short-lived
Drosophila flies in which the SOD gene, Sod, has beenknocked down 19).
Phenethylamine, a decarboxylated form ofphenylalanine, has recently been identified as a substance that
prolongs survival in Sod-knockdown Drosophila 19). When
hot water extract of chlorella ( WEC) and phenethylamine(PHA) were administered orally at 100 mg/kg and 10 μg/kg,
respectively, to CB57/b6 mice fed HFD, both doses resulted
in a decrease in plasma LDL-C and T C ( Fig. 5-a, b ) 14).
Furthermore, administration of PHA significantly
reduced the markers of liver damage (AST, ALT) (Fig. 5-c, d ),and TBARS levels in the liver (Fig. 4-b), indicating that

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In this report, animal experiments using mice haveshown that a decrease in GAPDH, which is highly abundantin cells, causes an increase of MGO, which is derived fromdihydroxyacetone phosphate, an isomer of substrate of
GAPDH, resulting in increased oxidative stress and impaired
liver function. The limiting enzyme in the glycolytic system
is kinases, i.e., phosphofructokinase. Nevertheless, thereason for the presence of large amounts of GAPDH in cells
has not been fully understood. The facts presented in thispaper suggest that excess GAPDH is present to prevent theformation of toxic SCAs from GAPDH substrates. Whether
this phenomenon occurs in other organs or in other animalmodels, especially in the human liver fed HFD, needs to beinvestigated in the future. If HFD in humans also causes a
decrease in GAPDH and an increase in the production of
SCAs in the liver, direct and indirect “ hits” by SCAs may

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Fig. 5. Effects of WEC and PHA on liver dysfunction in HFD feeding mice: Changes of blood plasma LDL-C, TC, AST, and ALT.

Blood plasma LDL-C ( a ) and TC ( b ), AST ( c ), and ALT ( d ) levels in mice fed ND, HFD, HFD with 100 mg/ kg body weight of WEC, and
HFD with 10 µg/kg body weight of PHA for 12 weeks. The figure was adapted with permission from Zheng et al. (Reference 14). LDL- C,
low-density lipoprotein-cholesterol; TC, total cholesterol; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HFD, high fat
diet; ND, normal diet; WEC, hot water extract of chlorella; PHA, phenethylamine.

_ 133 _

short Chain Aldehydes and GAPDHConflict of interest declaration

occur resulting in development of nonalcoholic hepatitis andother age-related diseases. The maintenance of cysteine incells may also be an indicator of the “ hits.”
The reason why GAPDH is decreased in the liverof HFD feeding mice is unknown. The cysteine residue
in GAPDH is known to undergo modifications such as
nitrosylation by nitric oxide (NO) 20) and succinylation by
fumaric acid 21). It is not known whether such modifications
are caused by HFD, but such modifications may be involvedin the reduction of GAPDH. Also, as mentioned above,
SCAs react with the thiol group of cysteine. The resulting
SCAs may have modified GAPDH. These modificationsof the thiol group of GAPDH may be the direct cause of
the decrease in GAPDH, while it is also possible that thedecrease in GAPDH due to other factors increased theSCAs, thus causing further GAPDH decrease. Alternatively,a very low dose (10 μg/kg body weight) of phenethylamine
maintains GAPDH in the liver of mice fed HFD. The reason
for this is also unknown. Elucidation of the mechanisms ofthese changes will provide important insights into glucose
metabolism and homeostasis of liver function.

This work was supported by the Integrated Research
for Agriculture and Interdisciplinary Fields, Ministry ofAgriculture, Fisheries and Forests, Japan (grant number
14532022). Part of this study was presented at the 25 t h
Meeting of Society for Glycative Stress Research on
September 10, 2022, Kyoto, Japan.

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