In enzymology, a pyruvate synthase (EC1.2.7.1) is an enzyme that catalyzes the interconversion of pyruvate and acetyl-CoA. It is also called pyruvate:ferredoxin oxidoreductase (PFOR).
The relevant equilibrium catalysed by PFOR is:
pyruvate + CoA + oxidized ferredoxin acetyl-CoA + CO2 + reduced ferredoxin
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]
Metronidazole, a wide-spectrum antibiotic that targets anaerobic organisms, receive electron from the reduced ferredoxin produced by PFOR, thus turning into highly reactive nitrous free radical that destroy DNA and other vital biomolecules. [8]
^Ragsdale SW (2003). "Pyruvate ferredoxin oxidoreductase and its radical intermediate". Chemical Reviews. 103 (6): 2333–2346. doi:10.1021/cr020423e. PMID12797832.
^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. PMC3795384. PMID24202339. 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]
^"Nitazoxanide Prescribing Information"(PDF). United States Food and Drug Administration. Romark Pharmaceuticals. 3 March 2004. pp. 1–9. Retrieved 3 January 2016.
^Brunton, Laurence L. (2011). Goodman & Gilman's the pharmacological basis of therapeutics (12th ed.). New York: McGraw-Hill medical. p. 1429. ISBN978-0-07-162442-8.
Charon MH, Volbeda A, Chabriere E, Pieulle L, Fontecilla-Camps JC (1999). "Structure and electron transfer mechanism of pyruvate:ferredoxin oxidoreductase". Curr. Opin. Struct. Biol. 9 (6): 663–9. doi:10.1016/S0959-440X(99)00027-5. PMID10607667.
