Pyruvate synthase

In enzymology, a pyruvate synthase (EC 1.2.7.1) is an enzyme that catalyzes the interconversion of pyruvate and acetyl-CoA. It is also called pyruvate:ferredoxin oxidoreductase (PFOR).

pyruvate synthase
pyruvate synthase dimer, Desulfovibrio africanus
Identifiers
EC number1.2.7.1
CAS number9082-51-3
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

The relevant equilibrium catalysed by PFOR is:

pyruvate + CoA + oxidized ferredoxin acetyl-CoA + CO2 + reduced ferredoxin

The 3 substrates of this enzyme are pyruvate, CoA, and oxidized ferredoxin, whereas its 3 products are acetyl-CoA, CO2, and reduced ferredoxin.

Function

This enzyme participates in 4 metabolic pathways: pyruvate metabolism, propanoate metabolism, butanoate metabolism, and reductive carboxylate cycle (CO
2 fixation).

Its major role is the extraction of reducing equivalents by the decarboxylation. In aerobic organisms, this conversion is catalysed by pyruvate dehydrogenase, also uses thiamine pyrophosphate (TPP) but relies on lipoate as the electron acceptor. Unlike the aerobic enzyme complex PFOR transfers reducing equivalents to flavins or iron-sulflur clusters. This process links glycolysis to the Wood–Ljungdahl pathway.

Nomenclature

This enzyme belongs to the family of oxidoreductases, specifically those acting on the aldehyde or oxo group of donor with an iron-sulfur protein as acceptor.[1] The systematic name of this enzyme class is pyruvate:ferredoxin 2-oxidoreductase (CoA-acetylating). Other names in common use include:

  • pyruvate oxidoreductase,
  • pyruvate synthetase,
  • pyruvate:ferredoxin oxidoreductase,
  • pyruvic-ferredoxin oxidoreductase.

Structure

PFOR adopts a dimeric structure, while each monomeric subunit is composed of one or multiple chain(s) of polypeptides.[1] Each monomeric subunit of PFOR consists of six domains binding one TPP molecule and three [4Fe-4S] clusters.[2]

Catalytic Mechanism

An PFOR reaction starts with the nucleophilic attack of C2 of TPP on the 2-oxo carbon of pyruvate, which forms a lactyl-TPP adduct. Next, the lactyl-TPP adduct releases the CO2 moiety, forming an anionic intermediate, which then transfer an electron to a [4Fe-4S] cluster. These steps lead to a stable radical intermediate that can be observed by electron paramagnetic resonance (EPR) experiments. The radical intermediate reacts with a CoA molecule, transfers another electron from the radical intermediate to a [4Fe-4S] cluster and forms an acetyl-CoA product.[3]

Inhibitors

References
  1. Gibson MI, Chen PYT, Drennan CL (2016). "A structural phylogeny for understanding 2-oxoacid oxidoreductase function". Current Opinion in Structural Biology. 41: 54–61. doi:10.1016/j.sbi.2016.05.011. PMC 5381805. PMID 27315560.
  2. Chen PYT, Aman H, Can M, Ragsdale SW, Drennan CL (2018). "Binding site for coenzyme A revealed in the structure of pyruvate:ferredoxin oxidoreductase from Moorella thermoacetica". Proc Natl Acad Sci U S A. 115 (15): 3846–3851. doi:10.1073/pnas.1722329115. PMC 5899475. PMID 29581263.
  3. Ragsdale SW (2003). "Pyruvate ferredoxin oxidoreductase and its radical intermediate". Chemical Reviews. 103 (6): 2333–2346. doi:10.1021/cr020423e. PMID 12797832.
  4. Di Santo N, Ehrisman J (2013). "Research perspective: potential role of nitazoxanide in ovarian cancer treatment. Old drug, new purpose?". Cancers (Basel). 5 (3): 1163–1176. doi:10.3390/cancers5031163. PMC 3795384. PMID 24202339. Nitazoxanide [NTZ: 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide] is a thiazolide antiparasitic agent with excellent activity against a wide variety of protozoa and helminths.  ... Nitazoxanide (NTZ) is a main compound of a class of broad-spectrum anti-parasitic compounds named thiazolides. It is composed of a nitrothiazole-ring and a salicylic acid moiety which are linked together by an amide bond ... NTZ is generally well tolerated, and no significant adverse events have been noted in human trials [13]. ... In vitro, NTZ and tizoxanide function against a wide range of organisms, including the protozoal species Blastocystis hominis, C. parvum, Entamoeba histolytica, G. lamblia and Trichomonas vaginalis [13]
  5. "Nitazoxanide Prescribing Information" (PDF). United States Food and Drug Administration. Romark Pharmaceuticals. 3 March 2004. pp. 1–9. Retrieved 3 January 2016.
  6. Warren CA, van Opstal E, Ballard TE, Kennedy A, Wang X, Riggins M, Olekhnovich I, Warthan M, Kolling GL, Guerrant RL, Macdonald TL, Hoffman PS (August 2012). "Amixicile, a novel inhibitor of pyruvate: ferredoxin oxidoreductase, shows efficacy against Clostridium difficile in a mouse infection model". Antimicrob. Agents Chemother. 56 (8): 4103–11. doi:10.1128/AAC.00360-12. PMC 3421617. PMID 22585229.
  7. Hoffman PS, Bruce AM, Olekhnovich I, Warren CA, Burgess SL, Hontecillas R, Viladomiu M, Bassaganya-Riera J, Guerrant RL, Macdonald TL (2014). "Preclinical studies of amixicile, a systemic therapeutic developed for treatment of Clostridium difficile infections that also shows efficacy against Helicobacter pylori". Antimicrob. Agents Chemother. 58 (8): 4703–12. doi:10.1128/AAC.03112-14. PMC 4136022. PMID 24890599.

Further reading


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