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 b y the multienzyme complex pyruvate dehydrogenase. In most anaerobes, the sa me reaction is usually catalyzed by a single enzyme, pyruvate:ferredoxin ox idoreductase (PFOR). Thus, PFOR is a potential target for drug design again st certain anaerobic pathogens. Here, we report the crystal structures of t he homodimeric Desulfovibrio africanus PFOR (data to 2.3 Angstrom resolutio n), and of its complex with pyruvate (3.0 Angstrom resolution). The structu res 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 elect ron transfer pathway. In addition, the PFOR-pyruvate complex structure show s the noncovalent fixation of the substrate before the catalytic reaction.