Crystal structures of the key anaerobic enzyme pyruvate: Ferredoxin oxidoreductase, free and in complex with pyruvate
Laboratoire de Cristallographie et de Cristallogénèse des Protéines, Institut de Biologie Structurale J.-P. Ebel CEA-CNRS, Grenoble, France. Nature Structural Biology
03/1999; 6(2):182-90. DOI: 10.1038/5870
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.
Available from: Eric Smith
- "produce a second molecule of oxaloacetate, completing the network-autocatalytic topology and making the cycle selfamplifying . The distinctive reaction in the rTCA pathway is a carbonyl insertion at a thioester (acetyl-CoA or succinyl-CoA), performed by a family of conserved ferredoxin-dependent oxidoreductases which are triple-Fe 4 S 4 -cluster proteins . "
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ABSTRACT: Metabolism displays striking and robust regularities in the forms of
modularity and hierarchy, whose composition may be compactly described. This
renders metabolic architecture comprehensible as a system, and suggests the
order in which layers of that system emerged. Metabolism also serves as the
foundation in other hierarchies, at least up to cellular integration including
bioenergetics and molecular replication, and trophic ecology. The
recapitulation of patterns first seen in metabolism, in these higher levels,
suggests metabolism as a source of causation or constraint on many forms of
organization in the biosphere.
We identify as modules widely reused subsets of chemicals, reactions, or
functions, each with a conserved internal structure. At the small molecule
substrate level, module boundaries are generally associated with the most
complex reaction mechanisms and the most conserved enzymes. Cofactors form a
structurally and functionally distinctive control layer over the small-molecule
substrate. Complex cofactors are often used at module boundaries of the
substrate level, while simpler ones participate in widely used reactions.
Cofactor functions thus act as "keys" that incorporate classes of organic
reactions within biochemistry.
The same modules that organize the compositional diversity of metabolism are
argued to have governed long-term evolution. Early evolution of core
metabolism, especially carbon-fixation, appears to have required few
innovations among a small number of conserved modules, to produce adaptations
to simple biogeochemical changes of environment. We demonstrate these features
of metabolism at several levels of hierarchy, beginning with the small-molecule
substrate and network architecture, continuing with cofactors and key conserved
reactions, and culminating in the aggregation of multiple diverse physical and
biochemical processes in cells.
Available from: PubMed Central
- "The X-ray crystal structure of the A 2 -type pyruvate:ferredoxin oxidoreductase from Desulfovibrio africanus has been determined byChabrì ere et al.   and shown to contain one thiamine pyrophosphate, one Mg 2+ , and three [4Fe-4S] clusters as prosthetic groups per protomer . The ab-/a 2 b 2 -type homologs from aerobic archaea inherently lack the Fe-S subunit/domain called δ, which harbors two [4Fe-4S] clusters  , presumably as an evolutionary consequence of one protein adaptation strategy occurring under permanently oxidative conditions. "
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ABSTRACT: The general importance of the Fe-S cluster prosthetic groups in biology is primarily attributable to specific features of iron and sulfur chemistry, and the assembly and interplay of the Fe-S cluster core with the surrounding protein is the key to in-depth understanding of the underlying mechanisms. In the aerobic and thermoacidophilic archaea, zinc-containing ferredoxin is abundant in the cytoplasm, functioning as a key electron carrier, and many Fe-S enzymes are produced to participate in the central metabolic and energetic pathways. De novo formation of intracellular Fe-S clusters does not occur spontaneously but most likely requires the operation of a SufBCD complex of the SUF machinery, which is the only Fe-S cluster biosynthesis system conserved in these archaea. In this paper, a brief introduction to the buildup and maintenance of the intracellular Fe-S world in aerobic and hyperthermoacidophilic crenarchaeotes, mainly Sulfolobus, is given in the biochemical, genetic, and evolutionary context.
Available from: Caroline M Plugge
- "All other known syntrophic propionate degraders oxidize propionate to acetate plus CO 2. They use the methylmalonyl-CoA pathway which generates per molecule propionate one ATP via substrate level phosphorylation and three electron pairs by: (i) oxidation of succinate to fumarate (E°′ = +30 mV), (ii) oxidation of malate to oxaloacetate (E°′ = -176 mV), and (iii) pyruvate conversion to acetyl- CoA and CO2 (E°′ = -470 mV) (Fig. 2). The latter step can easily be coupled to proton reduction (E°′ = -414 mV) or CO2 (E°′ = -432 mV) reduction (Thauer et al., 1977) via ferredoxin, as anaerobic bacteria generally contain pyruvate : ferredoxin oxidoreductases (Chabrière et al., 1999). Oxidation of succinate and malate with protons would require hydrogen partial pressures of 10 -15 and 10 -8 atm respectively (Schink, 1997). "
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