Glutaconate CoA-transferase from Acidaminococcus fermentans: the crystal structure reveals homology with other CoA-transferases

Jacob, Uwe; Mack, Matthias; Clausen, Tim; Huber, Robert; Buckel, Wolfgañg; Messerschmidt, Albrecht

doi:10.1016/s0969-2126(97)00198-6

Cited by 78 publications

(122 citation statements)

References 38 publications

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“…The very low level of sequence identity retained between the two domains (ϳ6%) suggests that this gene duplication event occurred in the distant past. A similar ancient gene duplication event has been postulated for the ␣-and ␤-subunits of GCT, which together form the active heterodimer (14).…”

Section: Monomer Structurementioning

confidence: 63%

“…Overall Fold-The structures of the individual YdiF domains closely resemble those of SCOT (16), the ␣-and ␤-subunits of the GCT heterodimer (14), and the ACT ␣-subunit (15), with a r.m.s. deviation of 1.4 -1.6 Å for the C␣ atoms in pairwise structural alignments.…”

Section: Comparisons With Family I Coa Transferasesmentioning

confidence: 96%

“…In all YdiF-related CoA transferases, the sequence motifs 333 EXGXXG 338 and 398 GXGG(A/F) 402 are conserved, with the former sequence containing the catalytic glutamate residue (10,46,47) and the latter forming the oxyanion hole (14). In those subunits that show electron density for CoA, Glu 333 adopts one of two extended orientations.…”

Section: Catalytic Sitementioning

confidence: 99%

“…In YdiF, these include the structurally conserved residue Gln 118 , and the non-conserved residues Gly 37 , Thr 69 , Gly 70 , His 95 , and Gln 99 . Additional residues proposed to participate in co-substrate binding in GCT (14) are part of the insertion region (76 -84) and are absent in YdiF. The shorter 341-347 loop in YdiF results in the cleft being more open and accessible to the cosubstrate, whereas in contrast, the longer loops in SCOT and ␤-GCT results in narrowing of the cleft.…”

Section: Comparisons With Family I Coa Transferasesmentioning

confidence: 99%

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Crystallographic Trapping of the Glutamyl-CoA Thioester Intermediate of Family I CoA Transferases

Rangarajan

Ajamian

et al. 2005

Journal of Biological Chemistry

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Coenzyme A is a cofactor utilized by as many as 4% of all enzymes for a diverse variety of biological functions, including cell-cell-mediated recognition, nerve impulse conductance, transcription, and fatty acid biosynthesis and degradation (1, 2). Mainly, these reactions involve the binding and transfer of an acyl group from one substrate to another as part of an enzymatic reaction; it has been noted that coenzyme A is the most prominent acyl group carrier in all living systems (3). Enzymecatalyzed reactions employing CoA thioesters can be divided into two categories, (i) those where the thioester carbonyl C atom reacts as an electrophile and (ii) those where the thioester ␣-carbon is deprotonated and reacts as a nucleophile, in Claisen enzymes (1). CoA transferases, which catalyze the reversible transfer of CoA from a donor CoA thioester to a carboxylic acid acceptor generating the free donor and a new acyl-CoA (Scheme 1), belong to the first category of enzymes. Among the large number of CoA transferases, much attention has focused on mitochondrial succinyl-CoA:3-oxoacid CoA-transferase (SCOT), 4 as its autosomal recessive deficiency in humans results in improper ketone body utilization causing episodic severe ketosis, hypoglycemia, and ultimately coma (4, 5).Three classes of CoA transferases have been defined based mainly on mechanistic and sequence criteria (6). Family I enzymes employ as acceptors 3-oxoacids, short-chain fatty acids, or glutaconate. These enzymes operate with a ping-pong kinetic mechanism and form a covalent thioester intermediate (7). The most thoroughly studied member of the Family I CoA transferases is SCOT. Family II consists of the multifunctional enzymes citrate or citramalate lyase, and unlike Family I enzymes, they do not form a covalent thioester intermediate. Family III enzymes have been discovered more recently, and are distinct both mechanistically (6, 8) and structurally (9) A wealth of biochemical and mechanistic data are available for SCOT, largely based on the pioneering studies of Jencks and collaborators (7,(11)(12)(13). These studies established a landmark for the concept of substrate binding energy utilization by an enzyme to effect catalysis, showing that SCOT utilizes its covalent (␥-glutamyl-CoA thioester) and noncovalent interactions with the CoA moiety of the acyl-CoA substrate differentially to reduce the Gibbs activation energy required for catalysis (13). The utilization of this binding energy for catalysis differs for different chemical moieties within the CoA cofactor, as well for the different steps along the reaction coordinate. Although crystal structures are available for three Family I CoA transferases, including glutaconate CoA transferase (GCT) from Acidaminococcus fermentens (14), acetate-CoA transferase (ACT, ␣-subunit) from Escherichia coli (15), and SCOT from pig heart (16, 17), no structure has yet been determined with bound substrate or product. The absence of an enzyme-substrate co-crystal structure for any Family I CoA transferase has prevented...

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Section: Monomer Structurementioning

confidence: 63%

Section: Comparisons With Family I Coa Transferasesmentioning

confidence: 96%

Section: Catalytic Sitementioning

confidence: 99%

Section: Comparisons With Family I Coa Transferasesmentioning

confidence: 99%

See 2 more Smart Citations

Crystallographic Trapping of the Glutamyl-CoA Thioester Intermediate of Family I CoA Transferases

Rangarajan

Ajamian

et al. 2005

Journal of Biological Chemistry

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“…39 SuccinylCoA:3-ketoacid CoA transferase consists of two domains, and the N-terminal domain covers the catalytic site on the C-terminal domain. Glutaconate CoA transferase is an octamer of single-domain subunits, and their interfaces cover the ligand molecule.…”

Section: Hybrid/mixturementioning

confidence: 99%

Alteration of oligomeric state and domain architecture is essential for functional transformation between transferase and hydrolase with the same scaffold

2009

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Transferases and hydrolases catalyze different chemical reactions and express different dynamic responses upon ligand binding. To insulate the ligand molecule from the surrounding water, transferases bury it inside the protein by closing the cleft, while hydrolases undergo a small conformational change and leave the ligand molecule exposed to the solvent. Despite these distinct ligand-binding modes, some transferases and hydrolases are homologous. To clarify how such different catalytic modes are possible with the same scaffold, we examined the solvent accessibility of ligand molecules for 15 SCOP superfamilies, each containing both transferase and hydrolase catalytic domains. In contrast to hydrolases, we found that nine superfamilies of transferases use two major strategies, oligomerization and domain fusion, to insulate the ligand molecules. The subunits and domains that were recruited by the transferases often act as a cover for the ligand molecule. The other strategies adopted by transferases to insulate the ligand molecule are the relocation of catalytic sites, the rearrangement of secondary structure elements, and the insertion of peripheral regions. These findings provide insights into how proteins have evolved and acquired distinct functions with a limited number of scaffolds.

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Ein alternativer Isovaleryl‐CoA‐Biosyntheseweg: Beteiligung einer bisher unbekannten 3‐Methylglutaconyl‐CoA‐Decarboxylase

Luxenburger

Müller

2012

Angewandte Chemie

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Glutaconate CoA-transferase from Acidaminococcus fermentans: the crystal structure reveals homology with other CoA-transferases

Cited by 78 publications

References 38 publications

Crystallographic Trapping of the Glutamyl-CoA Thioester Intermediate of Family I CoA Transferases

Crystallographic Trapping of the Glutamyl-CoA Thioester Intermediate of Family I CoA Transferases

Alteration of oligomeric state and domain architecture is essential for functional transformation between transferase and hydrolase with the same scaffold

Ein alternativer Isovaleryl‐CoA‐Biosyntheseweg: Beteiligung einer bisher unbekannten 3‐Methylglutaconyl‐CoA‐Decarboxylase

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