Flavoproteins are a class of enzymes catalyzing a very broad spectrum of redox processes by different chemical mechanisms. This review describes the best studied of these mechanisms and discusses factors possibly governing reactivity and specificity.

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Mechanisms of flavoprotein-catalyzed reactions.

beta-oxidation of fatty acids in mitochondria, peroxisomes, and bacteria: a century of continued progress.

Acyl-CoA dehydrogenases constitute a family of flavoproteins that catalyze the α,β-dehydrogenation of fatty acid acyl-CoA conjugates While they differ widely in their specificity, they share the same basic chemical mechanism of α,β-dehydrogenation Medium chain acyl-CoA dehydrogenase is probably the best-studied member of the class and serves as a model for the study of catalytic mechanisms Based on medium chain acyl-CoA dehydrogenase we discuss the main factors that bring about catalysis, promote specificity and determine the selective transfer of electrons to electron transferring flavoprotein The mechanism of α,β-dehydrogenation is viewed as a process in which the substrate αC-H and βC-H bonds are ruptured concertedly, the first hydrogen being removed by the active center base Glu376-COO– as an H+, the second being transferred as a hydride to the flavin N(5) position Hereby the pKa of the substrate αC-H is lowered from > 20 to ≈ 8 by the effect of specific hydrogen bonds Concomitantly, the pKa of Glu376-COO– is also raised to 8–9 due to the decrease in polarity brought about by substrate binding The kinetic sequence of medium chain acyl-CoA dehydrogenase is rather complex and involves several intermediates A prominent one is the molecular complex of reduced enzyme with the enoyl-CoA product that is characterized by an intense charge transfer absorption and serves as the point of transfer of electrons to the electron transferring flavoprotein These views are also discussed in the context of the accompanying paper on the three-dimensional properties of acyl-CoA dehydrogenases

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Acyl-CoA dehydrogenases - a mechanistic overview

Mitochondrial beta-oxidation involves a family of flavoproteins that introduce a C-C double bond into their fatty acyl-CoA substrates. Deficiencies of these acyl-CoA dehydrogenases lead to fatty acid oxidation disorders involving life-threatening episodes of metabolic derangement. This review focuses on the medium chain acyl-CoA dehydrogenase as the best-understood member of its class. The crystal structure of the enzyme and salient features of its substrate specificity and mechanism of action are summarized. The surprising observation of a catalytically essential amino acid residue that nevertheless is not conserved in the acyl-CoA dehydrogenase family is discussed.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fasebj.9.9.7601336

Structure and mechanism of action of the acyl-CoA dehydrogenases.

Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of derivatives of isovaleryl-CoA. It was the first organic acidemia recognized in humans and can cause significant morbidity and mortality. Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in severely affected individuals. Both intra- and interfamilial variability have been recognized. Initially, two phenotypes with either an acute neonatal or a chronic intermittent presentation were described. More recently, a third group of individuals with mild biochemical abnormalities who can be asymptomatic have been identified through newborn screening of blood spots by tandem mass spectrometry. IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. Human IVD has been purified from tissue and recombinant sources and its biochemical and physical properties have been extensively studied. Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. One missense mutation, 932C>T (A282V), is particularly common in patients identified through newborn screening with mild metabolite elevations and who have remained asymptomatic to date. This mutation leads to a partially active enzyme with altered catalytic properties; however, its effects on clinical outcome and the necessity of therapy are still unknown. A better understanding of the heterogeneity of this disease and the relevance of genotype/phenotype correlations to clinical management of patients are among the challenges remaining in the study of this disorder in the coming years.

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Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity

Mechanism of action of short-chain, medium-chain, and long-chain acyl-CoA dehydrogenases. Direct evidence for carbanion formation as an intermediate step using enzyme-catalyzed C-2 proton/deuteron exchange in the absence of C-3 exchange.

Y Ikeda

Papers

Mechanism of action of short-chain, medium-chain, and long-chain acyl-CoA dehydrogenases. Direct evidence for carbanion formation as an intermediate step using enzyme-catalyzed C-2 proton/deuteron exchange in the absence of C-3 exchange.