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In enzymology, sarcosine dehydrogenase (EC 1.5.8.3) is a mitochondrial enzyme that catalyzes the chemical reaction N-demethylation of sarcosine to give glycine. This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH group of donor with other acceptors. The systematic name of this enzyme class is sarcosine:acceptor oxidoreductase (demethylating). Other names in common use include sarcosine N-demethylase, monomethylglycine dehydrogenase, and sarcosine:(acceptor) oxidoreductase (demethylating). Sarcosine dehydrogenase is closely related to dimethylglycine dehydrogenase, which catalyzes the demethylation reaction of dimethylglycine to sarcosine. Both sarcosine dehydrogenase and dimethylglycine dehydrogenase use FAD as a cofactor. Sarcosine dehydrogenase is linked by electron-transferring flavoprotein (ETF) to the respiratory redox chain. The general chemical reaction catalyzed by sarcosine dehydrogenase is:

sarcosine + acceptor + H₂O ${\displaystyle \rightleftharpoons }$ glycine + formaldehyde + reduced acceptor

Structure

There is no crystal structure available for sarcosine dehydrogenase. Sarcosine dehydrogenase contains a covalently bound FAD group " linked via the 8 alpha position of the isoalloxazine ring to an imidazole N(3) of a histidine residue". The enzyme, according to Freisell Wr. et al., also contains non-heme iron in a ratio of 1 or 2 iron per 300000g of enzyme, and 0.5 mol of acid soluble sulfur suggesting that the electron transfer during the first step in the reaction might proceed through a different pathway than that of Fe-S clusters.

Mechanism

Sarcosine dehydrogenase, with sarcosine as its substrate, follows Michaelis–Menten kinetics and has a Km of 0.5 mM and a Vmax of 16 mmol/hr/mg protein. The enzyme is inhibited competitively by methoxyacetic acid, which has a Ki of 0.26 mM

The exact mechanism of sarcosine dehydrogenase is not available. However, according to the overall net reaction discussed in Honova.E, et al. paper:

• Sarcosine + H₂O + O₂ → glycine + formaldehyde + H₂O₂

the first step of the reaction might involve the transfer of a hydride on the N-methyl group of sarcosine onto FAD, allowing H₂O to attack the carbocation in order to form intermediate 1 (See figure 1). There is no deamination step. Instead, the demethylation of the N-methyl group on sarcosine occurs directly. The reduced FADH from the first step then is oxidized by O₂ to form H₂O₂.

The demethylation of sarcosine catalyzed by sarcosine dehydrogenase can proceed with or without the presence of tetrahydrofolate. Under anaerobic condition and without tetrahydrofolate, however, a free formaldehyde is formed after the N-demethylation of sarcosine. The reaction with 1 mole of sarcosine and 1 mole of FAD, under this condition, yields 1 mole of glycine and 1 mole of formaldehyde (See figure 2 for mechanism).

Under the presence of tetrahydrofolate, sarcosine dehydrogenase binds to tetrahydrofolate and convert tetrahydrofolate to 5,10-methylenetetrahydrofolate. Tetrahydrofolate here serves as a 1-carbon acceptor during the demethylation process (See figure 3 for mechanism).

Function

Sarcosine dehydrogenase is one of the enzymes in sarcosine metabolism, which catalyzes the demethylation of sarcosine to make glycine. It is preceded by dimethylglycine dehydrogenase which turns dimethylglycine into sarcosine. Glycine can also be turned into sarcosine by glycine N-methyltransferase. Since glycine is the production of sarcosine dehydrogenase catalyzed reaction, aside from sarcosine metabolism, the enzyme is also indirectly connected to the creatine cycle and the respiratory chain in the mitochondria (See figure 4 for pathway). Even so, the biological significance of sarcosine dehydrogenase beyond sarcosine metabolism is not entirely known. In a study of hereditary hemochromatosis using both wild type and HFE (gene) deficient mice fed with 2 percent carbonyl iron supplemented diet, sarcosine dehydrogenase was shown to be down-regulated in HFE deficient mice, but role sarcosine dehydrogenase in iron metabolism is unknown from the experiment conducted.

Disease relevance

Sarcosinemia

Sarcosinemia is an autosomal recessive disease caused by a mutation of the sarcosine dehydrogenase gene in the 9q33-q34 gene locus. This leads to a compromised sarcosine metabolism and causes the build-up of sarcosine in blood and urine, a condition known as sarcosinemia.

Prostate cancer

In addition to sarcosinaemia, sarcosine dehydrogenase also seems to play a role in the progression process of prostate cancer. The concentration of sarcosine, along with those of uracil, kynurenine, glycerol 3-phosphate, leucine and proline increases as prostate cancer progresses. Thus, sarcosine can be used as a potential biomarker for the detection of prostate cancer and for measuring the progress of the disease. As Sreekumar, A. et al.’s paper shows, the removal of sarcosine dehydrogenase from benign prostate epithelial cells increases the concentration of sarcosine and increase cancer cell invasions while the removal of either dimethylglycine dehydrogenase or glycine N-methyltransferase in prostate cancer cells decreases cell invasions. This demonstrates that sarcosine metabolism plays a key-role in prostate cancer cell invasion and migration. Sreekumar’s study suggests that sarcosine dehydrogenase and other enzymes in the sarcosine metabolism pathways could be potential therapeutic targets for prostate cancer. However, a study done by Jentzmik F. et al. by analyzing sarcosine level in 92 patients with prostate cancer draws a different conclusion: sarcosine cannot be used as an indicator and biomarker for prostate cancer.

See also

• Sarcosinemia
• Sarcosine
• Dimethylglycine dehydrogenase

References

1. Steenkamp DJ, Husain M (June 1982). "The effect of tetrahydrofolate on the reduction of electron transfer flavoprotein by sarcosine and dimethylglycine dehydrogenases". Biochem. J. 203 (3): 707–15. doi:10.1042/bj2030707. PMC 1158287. PMID 6180732.
2. ^ Leys D, Basran J, Scrutton NS (August 2003). "Channelling and formation of 'active' formaldehyde in dimethylglycine oxidase". EMBO J. 22 (16): 4038–48. doi:10.1093/emboj/cdg395. PMC 175785. PMID 12912903.
3. ^ Cook RJ, Misono KS, Wagner C (October 1985). "The amino acid sequences of the flavin-peptides of dimethylglycine dehydrogenase and sarcosine dehydrogenase from rat liver mitochondria". J. Biol. Chem. 260 (24): 12998–3002. doi:10.1016/S0021-9258(17)38827-0. PMID 4055729.
4. FRISELL WR, MACKENZIE CG (January 1962). "Separation and purification of sarcosine dehydrogenase and dimethylglycine dehydrogenase". J. Biol. Chem. 237: 94–8. doi:10.1016/S0021-9258(18)81367-9. PMID 13895406.
5. ^ Roth JP, Klinman JP (January 2003). "Catalysis of electron transfer during activation of O2 by the flavoprotein glucose oxidase". Proc. Natl. Acad. Sci. U.S.A. 100 (1): 62–7. doi:10.1073/pnas.252644599. PMC 404145. PMID 12506204.
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8. Sato M, Ohishi N, Yagi K (April 1979). "Identification of a covalently bound flavoprotein in rat liver mitochondria with sarcosine dehydrogenase". Biochem. Biophys. Res. Commun. 87 (3): 706–11. doi:10.1016/0006-291X(79)92016-3. PMID 454421.
9. ^ Porter DH, Cook RJ, Wagner C (December 1985). "Enzymatic properties of dimethylglycine dehydrogenase and sarcosine dehydrogenase from rat liver". Arch. Biochem. Biophys. 243 (2): 396–407. doi:10.1016/0003-9861(85)90516-8. PMID 2417560.
10. Honová E, Drahota Z, Hahn P (August 1967). "Sarcosine dehydrogenase activity in liver mitochondria of infant and adult rats". Experientia. 23 (8): 632–3. doi:10.1007/bf02144166. PMID 6051684. S2CID 32369212.
11. Wittwer AJ, Wagner C (August 1980). "Identification of folate binding protein of mitochondria as dimethylglycine dehydrogenase". Proc. Natl. Acad. Sci. U.S.A. 77 (8): 4484–8. doi:10.1073/pnas.77.8.4484. PMC 349868. PMID 6159630.
12. MITOMA C, GREENBERG DM (May 1952). "Studies on the mechanism of the biosynthesis of serine". J. Biol. Chem. 196 (2): 599–614. doi:10.1016/S0021-9258(19)52395-X. PMID 12981004.
13. ^ Sreekumar A, Poisson LM, Rajendiran TM, et al. (February 2009). "Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression" (PDF). Nature. 457 (7231): 910–4. doi:10.1038/nature07762. hdl:2027.42/62661. PMC 2724746. PMID 19212411.
14. ^ Wyss M, Kaddurah-Daouk R (July 2000). "Creatine and creatinine metabolism". Physiol. Rev. 80 (3): 1107–213. doi:10.1152/physrev.2000.80.3.1107. PMID 10893433.
15. ^ Glorieux FH, Scriver CR, Delvin E, Mohyuddin F (November 1971). "Transport and metabolism of sarcosine in hypersarcosinemic and normal phenotypes". J. Clin. Invest. 50 (11): 2313–22. doi:10.1172/JCI106729. PMC 292173. PMID 5096515.
16. ^ Moolenaar SH, Poggi-Bach J, Engelke UF, et al. (April 1999). "Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: NMR spectroscopy study". Clin. Chem. 45 (4): 459–64. doi:10.1093/clinchem/45.4.459. PMID 10102904.
17. Petrak J, Myslivcova D, Halada P, et al. (2007). "Iron-independent specific protein expression pattern in the liver of HFE-deficient mice". Int. J. Biochem. Cell Biol. 39 (5): 1006–15. doi:10.1016/j.biocel.2007.01.021. PMID 17376729.
18. Eschenbrenner M, Jorns MS (August 1999). "Cloning and mapping of the cDNA for human sarcosine dehydrogenase, a flavoenzyme defective in patients with sarcosinemia". Genomics. 59 (3): 300–8. doi:10.1006/geno.1999.5886. PMID 10444331.
19. Baum CE, Price DK, Figg WD (March 2010). "Sarcosine as a potential prostate cancer biomarker and therapeutic target". Cancer Biol. Ther. 9 (5): 341–2. doi:10.4161/cbt.9.5.11310. PMC 2874119. PMID 20150759.
20. Jentzmik F, Stephan C, Lein M, et al. (February 2011). "Sarcosine in prostate cancer tissue is not a differential metabolite for prostate cancer aggressiveness and biochemical progression". J. Urol. 185 (2): 706–11. doi:10.1016/j.juro.2010.09.077. PMID 21168877.

Further reading

• FRISELL WR, MACKENZIE CG (1962). "Separation and purification of sarcosine dehydrogenase and dimethylglycine dehydrogenase". J. Biol. Chem. 237: 94–8. doi:10.1016/S0021-9258(18)81367-9. PMID 13895406.
• HOSKINS DD, MACKENZIE CG (1961). "Solubilization and electron transfer flavoprtein requirement of mitochondrial sarcosine dehydrogenase and dimethylglycine dehydrogenase". J. Biol. Chem. 236: 177–83. doi:10.1016/S0021-9258(18)64450-3. PMID 13716069.

• Biology

• EC 1.5.8
• Flavoproteins
• Enzymes of unknown structure