In
enzymology
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
, sarcosine dehydrogenase () is a mitochondrial
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that
catalyzes
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
the
chemical reaction
A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...
N-demethylation of
sarcosine
Sarcosine, also known as ''N''-methylglycine, or monomethylglycine, is a monopeptide with the formula CH3N(H)CH2CO2H. It exists at neutral pH as the zwitterion CH3N+(H)2CH2CO2−, which can be obtained as a white, water-soluble powder. Like some ...
to give
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
.
This enzyme belongs to the family of
oxidoreductase
In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually ut ...
s, specifically those acting on the CH-NH group of donor with other acceptors. The
systematic name A systematic name is a name given in a systematic way to one unique group, organism, object or chemical substance, out of a specific population or collection. Systematic names are usually part of a nomenclature.
A semisystematic name or semitrivial ...
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
Dimethylglycine (DMG) is a derivative of the amino acid glycine with the structural formula (CH3)2NCH2COOH. It can be found in beans and liver, and has a sweet taste. It can be formed from trimethylglycine upon the loss of one of its methyl groups ...
to
sarcosine
Sarcosine, also known as ''N''-methylglycine, or monomethylglycine, is a monopeptide with the formula CH3N(H)CH2CO2H. It exists at neutral pH as the zwitterion CH3N+(H)2CH2CO2−, which can be obtained as a white, water-soluble powder. Like some ...
. Both sarcosine dehydrogenase and dimethylglycine dehydrogenase use
FAD
A fad or trend is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse for a short period.
Fads are objects or behaviors that achieve short- ...
as a cofactor. Sarcosine dehydrogenase is linked by
electron-transferring flavoprotein
An electron transfer flavoprotein (ETF) or electron transfer flavoprotein complex (CETF) is a flavoprotein located on the matrix face of the inner mitochondrial membrane and functions as a specific electron acceptor for primary dehydrogenases, tra ...
(ETF) to the respiratory redox chain.
The general chemical reaction catalyzed by sarcosine dehydrogenase is:
:sarcosine + acceptor + H
2O
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
In biochemistry, Michaelis–Menten kinetics is one of the best-known models of enzyme kinetics. It is named after German biochemist Leonor Michaelis and Canadian physician Maud Menten. The model takes the form of an equation describing the rate ...
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 + H
2O + O
2 → glycine +
formaldehyde
Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...
+ H
2O
2
the first step of the reaction might involve the transfer of a hydride on the N-methyl group of sarcosine onto FAD, allowing H
2O 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 O
2 to form H
2O
2.
The demethylation of sarcosine catalyzed by sarcosine dehydrogenase can proceed with or without the presence of
tetrahydrofolate
Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative.
Metabolism
Human synthesis
Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate.
It is co ...
.
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
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
. It is preceded by
dimethylglycine dehydrogenase which turns
dimethylglycine
Dimethylglycine (DMG) is a derivative of the amino acid glycine with the structural formula (CH3)2NCH2COOH. It can be found in beans and liver, and has a sweet taste. It can be formed from trimethylglycine upon the loss of one of its methyl groups ...
into sarcosine. Glycine can also be turned into sarcosine by
glycine N-methyltransferase
In enzymology, a glycine N-methyltransferase () is an enzyme that catalyzes the chemical reaction
:S-adenosyl-L-methionine + glycine \rightleftharpoons S-adenosyl-L-homocysteine + sarcosine
Thus, the substrates of this enzyme are S-adenosyl met ...
.
Since glycine is the production of sarcosine dehydrogenase catalyzed reaction, aside from sarcosine metabolism, the enzyme is also indirectly connected to the
creatine
Creatine ( or ) is an organic compound with the nominal formula (H2N)(HN)CN(CH3)CH2CO2H. It exists in various modifications (tautomers) in solution. Creatine is found in vertebrates where it facilitates recycling of adenosine triphosphate ( ...
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
Hereditary haemochromatosis type 1 (HFE-related Hemochromatosis) is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, h ...
using both wild type and
HFE (gene)
Human homeostatic iron regulator protein, also known as the HFE protein (High FE2+), is a protein which in humans is encoded by the ''HFE'' gene. The ''HFE'' gene is located on short arm of chromosome 6 at location 6p22.2
Function
The protein ...
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
Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
. The concentration of sarcosine, along with those of
uracil
Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced by ...
,
kynurenine
-Kynurenine is a metabolite of the amino acid -tryptophan used in the production of niacin.
Kynurenine is synthesized by the enzyme tryptophan dioxygenase, which is made primarily but not exclusively in the liver, and indoleamine 2,3-dioxygenase ...
,
glycerol 3-phosphate
''sn''-Glycerol 3-phosphate is the organic ion with the formula HOCH2CH(OH)CH2OPO32-. It is one of three stereoisomers of the ester of dibasic phosphoric acid (HOPO32-) and glycerol. It is a component of glycerophospholipids. Equally appropriat ...
,
leucine
Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- ca ...
and
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
increases as
prostate cancer
Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
progresses. Thus, sarcosine can be used as a potential
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
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
Malignancy () is the tendency of a medical condition to become progressively worse.
Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malign ...
prostate
epithelial cells
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
increases the concentration of sarcosine and increase cancer cell invasions while the removal of either dimethylglycine dehydrogenase or
glycine N-methyltransferase
In enzymology, a glycine N-methyltransferase () is an enzyme that catalyzes the chemical reaction
:S-adenosyl-L-methionine + glycine \rightleftharpoons S-adenosyl-L-homocysteine + sarcosine
Thus, the substrates of this enzyme are S-adenosyl met ...
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
Sarcosine, also known as ''N''-methylglycine, or monomethylglycine, is a monopeptide with the formula CH3N(H)CH2CO2H. It exists at neutral pH as the zwitterion CH3N+(H)2CH2CO2−, which can be obtained as a white, water-soluble powder. Like some ...
*
Dimethylglycine dehydrogenase
References
Further reading
*
*
{{Portal bar, Biology, border=no
EC 1.5.8
Flavin enzymes
Enzymes of unknown structure