Crystal structures of the key anaerobic enzyme pyruvate:ferredoxin oxidoreductase, free and in complex with pyruvate.
Oxidative decarboxylation of pyruvate to form acetyl-coenzyme A, a crucial step in many metabolic pathways, is carried out in most aerobic organisms by the multienzyme complex pyruvate dehydrogenase. In most anaerobes, the same reaction is usually catalyzed by a single enzyme, pyruvate:ferredoxin oxidoreductase (PFOR). Thus, PFOR is a potential target for drug design against certain anaerobic pathogens. Here, we report the crystal structures of the homodimeric Desulfovibrio africanus PFOR (data to 2.3 A resolution), and of its complex with pyruvate (3.0 A resolution). The structures show that each subunit consists of seven domains, one of which affords protection against oxygen. The thiamin pyrophosphate (TPP) cofactor and the three [4Fe-4S] clusters are suitably arranged to provide a plausible electron transfer pathway. In addition, the PFOR-pyruvate complex structure shows the noncovalent fixation of the substrate before the catalytic reaction.
Chabrière
E
E
Laboratoire de Cristallographie et de Cristallogénèse des Protéines, Institut de Biologie Structurale J.-P. Ebel CEA-CNRS, Grenoble, France.
Charon
M H
MH
Volbeda
A
A
Pieulle
L
L
Hatchikian
E C
EC
Fontecilla-Camps
J C
JC
D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D004583:Electrons; D004789:Enzyme Activation; D007658:Ketone Oxidoreductases / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D010100:Oxygen / Q000737:chemistry; D011487:Protein Conformation; D050743:Pyruvate Synthase; D019289:Pyruvic Acid / Q000737:chemistry*
D019289:Pyruvic Acid; D007658:Ketone Oxidoreductases; D050743:Pyruvate Synthase; D010100:Oxygen