“…In CII, it is even covalently and thus permanently bound to the enzyme during the catalytic cycle when the redox state is regenerated in each enzymatic turnover, as documented in early reports ( 35 ) and summarized in classical textbooks ( 36 , 37 ). Structural studies of CII have expanded our knowledge of the mechanism of enzyme assembly ( 13 ), enzyme structure ( 38 , 39 , 40 ), kinetic regulation of CII activity ( 41 , 42 ), and associated pathologies ( 3 , 26 , 27 , 28 , 29 ).…”
Section: Electron Flow Through CI and Cii To The Coenzyme Q Junctionmentioning
“…In CII, it is even covalently and thus permanently bound to the enzyme during the catalytic cycle when the redox state is regenerated in each enzymatic turnover, as documented in early reports ( 35 ) and summarized in classical textbooks ( 36 , 37 ). Structural studies of CII have expanded our knowledge of the mechanism of enzyme assembly ( 13 ), enzyme structure ( 38 , 39 , 40 ), kinetic regulation of CII activity ( 41 , 42 ), and associated pathologies ( 3 , 26 , 27 , 28 , 29 ).…”
Section: Electron Flow Through CI and Cii To The Coenzyme Q Junctionmentioning
“… Figure 4 Diversity in structure and megastructure across the greater complex II family. Complex II enzymes are currently categorized into six recognized classes based on their membrane-spanning regions ( 83 ). Most members of the complex II superfamily contain a soluble domain with two subunits and between one and three membrane-spanning subunits, although Class B members are believed to peripheral-membrane enzymes and there are fully soluble homologs.…”
Section: Membrane Protein Crystallography and Structure-function Appr...mentioning
confidence: 99%
“…These distinct complex II structures represent five of the six recognized evolutionary subclasses of complex II ( Fig. 4 , A – F ) ( 83 ).…”
Section: Membrane Protein Crystallography and Structure-function Appr...mentioning
confidence: 99%
“…Why would complex II have such diverse functions and such plasticity in its structural assemblies? Complex II is an evolutionarily ancient enzyme with ancestors that likely supported respiration before oxygen became abundant on the planet ( 83 ). Phylogeny hints that major changes in complex II rapidly occurred around the time of the great oxidation event ( 2 , 204 , 205 ).…”
Section: Integration Over Time: An Evolving Viewmentioning
“…5 These enzymes also have biotechnological relevance as ene-reductases for stereoselective hydrogenations. 6 While their origin can be traced to a single soluble protein ancestor, 7,8 membrane-bound FRD/SDH enzymes found in prokaryotes and in the inner mitochondrial membrane have evolved to multimeric complexes with iron−sulfur proteins and transmembrane subunits. 1 Soluble FRDs are monomeric and found in bacterial periplasm 9 and various cellular compartments.…”
The interconversion between fumarate and succinate is
fundamental
to the energy metabolism of nearly all organisms. This redox reaction
is catalyzed by a large family of enzymes, fumarate reductases and
succinate dehydrogenases, using hydride and proton transfers from
a flavin cofactor and a conserved Arg side-chain. These flavoenzymes
also have substantial biomedical and biotechnological importance.
Therefore, a detailed understanding of their catalytic mechanisms
is valuable. Here, calibrated electronic structure calculations in
a cluster model of the active site of the Fcc3 fumarate
reductase were employed to investigate various reaction pathways and
possible intermediates in the enzymatic environment and to dissect
interactions that contribute to catalysis of fumarate reduction. Carbanion,
covalent adduct, carbocation, and radical intermediates were examined.
Significantly lower barriers were obtained for mechanisms via carbanion
intermediates, with similar activation energies for hydride and proton
transfers. Interestingly, the carbanion bound to the active site is
best described as an enolate. Hydride transfer is stabilized by a
preorganized charge dipole in the active site and by the restriction
of the C1–C2 bond in a twisted conformation of the otherwise
planar fumarate dianion. But, protonation of a fumarate carboxylate
and quantum tunneling effects are not critical for catalysis of the
hydride transfer. Calculations also suggest that the driving force
for enzyme turnover is provided by regeneration of the catalytic Arg,
either coupled with flavin reduction and decomposition of a proposed
transient state or directly from the solvent. The detailed mechanistic
description of enzymatic reduction of fumarate provided here clarifies
previous contradictory views and provides new insights into catalysis
by essential flavoenzyme reductases and dehydrogenases.
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