Sarcosine dehydrogenase

Source: Wikipedia, the free encyclopedia.
Sarcosine dehydrogenase
Identifiers
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

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.[1] 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.[2]
The general chemical reaction catalyzed by sarcosine dehydrogenase is:

sarcosine + acceptor + H2O 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".[3] 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,[4] 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.[3]

Mechanism

Figure 1: First step in sarcosine dehydrogenase catalyzed reaction mechanism[5]
Figure 2: Sarcosine going to glycine reaction mechanism without THF present.[6]
tetrahydrofolate (THF) present.[7]

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.[8] The enzyme is inhibited competitively by methoxyacetic acid, which has a Ki of 0.26 mM [9]

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

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.[6] The reduced FADH− from the first step then is oxidized by O2 to form H2O2.[5]

The demethylation of sarcosine catalyzed by sarcosine dehydrogenase can proceed with or without the presence of

tetrahydrofolate.[11] Under anaerobic condition and without tetrahydrofolate, however, a free formaldehyde is formed after the N-demethylation of sarcosine.[12] 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).[9]

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).[2]

Function

Sarcosine dehydrogenase is one of the enzymes in sarcosine metabolism, which catalyzes the demethylation of sarcosine to make

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.[17]

Figure 4: Sarcosine metabolism and related pathway.[14][15][16]

Disease relevance

Sarcosinemia

autosomal recessive disease caused by a mutation of the sarcosine dehydrogenase gene in the 9q33-q34 gene locus.[18] 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

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.[13] 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.[20]

See also

References

  1. PMID 6180732
    .
  2. ^
    PMID 12912903
    .
  3. ^
    PMID 4055729
    .
  4. PMID 13895406
    .
  5. ^
    PMID 12506204
    .
  6. ^ a b "www.jbc.org" (PDF).
  7. PMID 14403792
    .
  8. PMID 454421
    .
  9. ^
    PMID 2417560
    .
  10. S2CID 32369212
    .
  11. PMID 6159630
    .
  12. PMID 12981004
    .
  13. ^
    PMID 19212411
    .
  14. ^
    PMID 10893433
    .
  15. ^
    PMID 5096515
    .
  16. ^
    PMID 10102904
    .
  17. PMID 17376729
    .
  18. PMID 10444331
    .
  19. PMID 20150759
    .
  20. PMID 21168877
    .

Further reading
Retrieved from "https://en.wikipedia.org/w/index.php?title=Sarcosine_dehydrogenase&oldid=1172360462"