3-mercaptopyruvate sulfurtransferase

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3-mercaptopyruvate sulfurtransferase
PDB 3OLH mercaptopyruvate sulfurtransferase.png
Crystallographic structure of 3-mercaptopyruvate sulfurtransferase based on PDB: 3OLH ​. Rainbow colored (N-terminus blue and C-terminus red). The catalytic cysteine is depicted by spheres.
Identifiers
EC no. 2.8.1.2
CAS no. 9026-05-5
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
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PMC articles
PubMed articles
NCBI proteins
3-mercaptopyruvate sulfurtransferase
Identifiers
SymbolMPST
Alt. symbolsMST, TST2, TUM1
Alt. nameshuman liver rhodanese
NCBI gene 4357
HGNC 7223
OMIM 602496
PDB 3OLH
RefSeq NP_066949
UniProt P25325
Other data
EC number 2.8.1.2
Locus Chr. 22 q123
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Structures Swiss-model
Domains InterPro

In enzymology, a 3-mercaptopyruvate sulfurtransferase (EC 2.8.1.2) is an enzyme that catalyzes the chemical reactions of 3-mercaptopyruvate. This enzyme belongs to the family of transferases, specifically the sulfurtransferases. [1] This enzyme participates in cysteine metabolism. It is encoded by the MPST gene. [2]

Contents

The enzyme is of interest because it provides a pathway for detoxification of cyanide, especially since it occurs widely in the cytosol and distributed broadly. [3]

Nomenclature

The systematic name of this enzyme class is 3-mercaptopyruvate:cyanide sulfurtransferase. This enzyme is also called beta-mercaptopyruvate sulfurtransferase and in the older literature, human liver rhodanese. [4]

Structure

Gene

The MPST gene lies on the chromosome location of 22q12.3 and consists of 6 exons. Alternatively spliced transcript variants encoding the same protein have been identified. [2] [5]

Protein

The encoded cytoplasmic protein is a member of the rhodanese family but is not rhodanese itself, which is found only in mitochondria. MPST protein consists of 317 amino acid residues and weighs 35250Da. MPST contains two rhodanese domains with similar secondary structures suggesting a common evolutionary origin. The catalytic cysteine residue only exists in the C-terminal rhodanese domain. The protein can function as a monomer or as a disulfide-linked homodimer.

Function and mechanism

The biological function of MPST remains unclear. It may be involved in cyanide detoxification, biosynthesis of thiosulfate, production of the signalling molecule hydrogen sulfide, or the degradation of cysteine.

MPST reacts with 3-MP to convert a cysteinyl residue to the persulfide-containing intermediate: [3]

RSH + HSCH2C(O)CO2− → RSSH + CH3C(O)CO2−

The persulfide group is labile, and can transfer S to other groups, such as cyanide. It is also susceptible to reduction to release hydrogen sulfide.

H2S is produced from l-cysteine by cystathionine-γ-lyase (CSE) and MPST. l-cysteine-dependent production of H2S by MPST is a two-step reaction. In the first step, cysteine transaminase converts l-cysteine along with α-ketoglutarate into 3-mercaptopyruvate (3-MP). Subsequently, MPST converts 3-MP into H2S. [6] MPST catalyzes the transfer of a sulfur atom from mercaptopyruvate to sulfur acceptors like cyanides or thiol compounds. [7] Thus it is also considered to participate in cysteine degradation. [5] MPST generates H2S in coronary artery, mediating its effects through direct modulation of NO, namely vasodilation. This has important implications for H2S-based therapy in healthy and diseased coronary arteries. [8]

Biological significance

MPST is expressed in a number of tissues, including kidney, liver, lung, heart, muscle, spleen, and brain. [9] [10] [11]

3-Mercaptopyruvate (3-MP), along with α-ketoglutarate, is derived from cysteine by the action of an aminotransferase. Thus MPST may participate in cysteine degradation.

Biomedical

Hydrogen sulfide production

H2S is produced from MPST (as well as by cystathionine-γ-lyase). [6] [1] MPST generates H2S in coronary artery, mediating its effects through direct modulation of NO, namely vasodilation. This has important implications for H2S-based therapy in healthy and diseased coronary arteries. [8]

Mercaptolactate-cysteine disulfiduria

Deficiency in MPST has been found related to mercaptolactate-cysteine disulfiduria (or Ampola syndrome), a rare inheritable disorder associated with oversecretion of mercaptolactate-cysteine disulfide in urine. [12] Fewer than 1,000 people have this rare disorder in the United States. [13] Symptoms and signs include: high forehead, seizures, arachnodactyly, genu valgum, hypolasia of the ear cartilage and umbilical hernia.

Bladder cancer

Immunoreactivity for MPST was detected in malignant uroepithelium and muscular layer of bladder cancer samples. Protein levels and catalytic activities of MPST increased with the increase of malignant degrees in human bladder tissues and human urothelial cell carcinoma of bladder (UCB) cell lines and this may promote the application of MPST novel enzymes to UCB diagnosis or treatment. [14]

Related Research Articles

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<span class="mw-page-title-main">Methionine</span> Sulfur-containing amino acid

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<span class="mw-page-title-main">Glutathione</span> Ubiquitous antioxidant compound in living organisms

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<span class="mw-page-title-main">Hydrogen sulfide</span> Poisonous, corrosive and flammable gas

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<span class="mw-page-title-main">Cysteine dioxygenase</span> Enzyme

Cysteine dioxygenase (CDO) is a non-heme iron enzyme that catalyzes the conversion of L-cysteine to cysteine sulfinic acid. CDO plays an important role in cysteine catabolism, regulating intracellular levels of cysteine and responding changes in cysteine availability. As such, CDO is highly regulated and undergoes large changes in concentration and efficiency. It oxidizes cysteine to the corresponding sulfinic acid by activation of dioxygen, although the exact mechanism of the reaction is still unclear. In addition to being found in mammals, CDO also exists in some yeast and bacteria, although the exact function is still unknown. CDO has been implicated in various neurodegenerative diseases and cancers, which is likely related to cysteine toxicity.

Iron–sulfur proteins are proteins characterized by the presence of iron–sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states. Iron–sulfur clusters are found in a variety of metalloproteins, such as the ferredoxins, as well as NADH dehydrogenase, hydrogenases, coenzyme Q – cytochrome c reductase, succinate – coenzyme Q reductase and nitrogenase. Iron–sulfur clusters are best known for their role in the oxidation-reduction reactions of electron transport in mitochondria and chloroplasts. Both Complex I and Complex II of oxidative phosphorylation have multiple Fe–S clusters. They have many other functions including catalysis as illustrated by aconitase, generation of radicals as illustrated by SAM-dependent enzymes, and as sulfur donors in the biosynthesis of lipoic acid and biotin. Additionally, some Fe–S proteins regulate gene expression. Fe–S proteins are vulnerable to attack by biogenic nitric oxide, forming dinitrosyl iron complexes. In most Fe–S proteins, the terminal ligands on Fe are thiolate, but exceptions exist.

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<span class="mw-page-title-main">Rhodanese</span> Mitochondrial enzyme which breaks down cyanide

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<span class="mw-page-title-main">Sulfite reductase</span> Enzyme family

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<span class="mw-page-title-main">TST (gene)</span> Protein-coding gene in the species Homo sapiens

Thiosulfate sulfurtransferase is an enzyme that in humans is encoded by the TST gene.

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References

  1. 1 2 Yadav PK, Yamada K, Chiku T, Koutmos M, Banerjee R (July 2013). "Structure and kinetic analysis of H2S production by human mercaptopyruvate sulfurtransferase". The Journal of Biological Chemistry. 288 (27): 20002–13. doi: 10.1074/jbc.M113.466177 . PMC   3707699 . PMID   23698001.
  2. 1 2 "Entrez Gene: MPST mercaptopyruvate sulfurtransferase".
  3. 1 2 Patterson SE, Moeller B, Nagasawa HT, Vince R, Crankshaw DL, Briggs J, Stutelberg MW, Vinnakota CV, Logue BA (June 2016). "Development of sulfanegen for mass cyanide casualties". Annals of the New York Academy of Sciences. 1374 (1): 202–9. Bibcode:2016NYASA1374..202P. doi:10.1111/nyas.13114. PMC   4940216 . PMID   27308865.
  4. ↑ Pallini R, Guazzi GC, Cannella C, Cacace MG (October 1991). "Cloning and sequence analysis of the human liver rhodanese: comparison with the bovine and chicken enzymes". Biochemical and Biophysical Research Communications. 180 (2): 887–93. doi: 10.1016/S0006-291X(05)81148-9 . PMID   1953758.
  5. 1 2 Nagahara N, Okazaki T, Nishino T (July 1995). "Cytosolic mercaptopyruvate sulfurtransferase is evolutionarily related to mitochondrial rhodanese. Striking similarity in active site amino acid sequence and the increase in the mercaptopyruvate sulfurtransferase activity of rhodanese by site-directed mutagenesis". The Journal of Biological Chemistry. 270 (27): 16230–5. doi: 10.1074/jbc.270.27.16230 . PMID   7608189.
  6. 1 2 Shibuya N, Mikami Y, Kimura Y, Nagahara N, Kimura H (November 2009). "Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide". Journal of Biochemistry. 146 (5): 623–6. doi:10.1093/jb/mvp111. PMID   19605461.
  7. ↑ Vachek H, Wood JL (January 1972). "Purification and properties of mercaptopyruvate sulfur transferase of Escherichia coli". Biochimica et Biophysica Acta (BBA) - Enzymology. 258 (1): 133–46. doi:10.1016/0005-2744(72)90973-4. PMID   4550801.
  8. 1 2 Kuo MM, Kim DH, Jandu S, Bergman Y, Tan S, Wang H, Pandey DR, Abraham TP, Shoukas AA, Berkowitz DE, Santhanam L (January 2016). "MPST but not CSE is the primary regulator of hydrogen sulfide production and function in the coronary artery". American Journal of Physiology. Heart and Circulatory Physiology. 310 (1): H71–9. doi:10.1152/ajpheart.00574.2014. PMC   4796461 . PMID   26519030.
  9. ↑ Billaut-Laden I, Rat E, Allorge D, Crunelle-Thibaut A, Cauffiez C, Chevalier D, Lo-Guidice JM, Broly F (August 2006). "Evidence for a functional genetic polymorphism of the human mercaptopyruvate sulfurtransferase (MPST), a cyanide detoxification enzyme". Toxicology Letters. 165 (2): 101–11. doi:10.1016/j.toxlet.2006.02.002. PMID   16545926.
  10. ↑ Ubuka T, Hosaki Y, Nishina H, Ikeda T (1985). "3-Mercaptopyruvate sulfurtransferase activity in guinea pig and rat tissues". Physiological Chemistry and Physics and Medical NMR. 17 (1): 41–3. PMID   3862140.
  11. ↑ Nagahara N, Ito T, Kitamura H, Nishino T (September 1998). "Tissue and subcellular distribution of mercaptopyruvate sulfurtransferase in the rat: confocal laser fluorescence and immunoelectron microscopic studies combined with biochemical analysis". Histochemistry and Cell Biology. 110 (3): 243–50. doi:10.1007/s004180050286. PMID   9749958. S2CID   25430792.
  12. ↑ Sörbo B (1987). "3-Mercaptopyruvate, 3-mercaptolactate and mercaptoacetate". Sulfur and Sulfur Amino Acids. Methods in Enzymology. Vol. 143. pp. 178–82. doi:10.1016/0076-6879(87)43033-4. ISBN   9780121820435. PMID   3657534.
  13. ↑ "Beta-mercaptolactate cysteine disulfiduria - About the Disease - Genetic and Rare Diseases Information Center". rarediseases.info.nih.gov. Retrieved 2024-03-09.
  14. ↑ Gai JW, Qin W, Liu M, Wang HF, Zhang M, Li M, Zhou WH, Ma QT, Liu GM, Song WH, Jin J, Ma HS (April 2016). "Expression profile of hydrogen sulfide and its synthases correlates with tumor stage and grade in urothelial cell carcinoma of bladder". Urologic Oncology. 34 (4): 166.e15–20. doi:10.1016/j.urolonc.2015.06.020. PMID   26847849.

Further reading (mainly older literature)

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