[53] Isopropylmalate dehydratase from yeast

Kohlhaw, Gunter B.

doi:10.1016/s0076-6879(88)66055-1

Cited by 52 publications

(50 citation statements)

References 13 publications

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“…Therefore the crystallized P. horikoshii homolog is probably an HACN and not an IPMI subunit as proposed previously (45). An unrefined homology model of the MJ1277 protein produced by the SWISS-MODEL server (version 36.0003) (32) based on the P. horikoshii protein structure suggests that Leu 27 and His 71 side chains of MJ0277 form a hydrophobic pocket that could confer specificity for short alkyl-substituted hydroxy-dicarboxylates.…”

Section: Discussionmentioning

confidence: 59%

“…The isomerase and dehydrogenase enzymes that catalyze successive reactions have not been characterized from those organisms as pure proteins. Because the leucine biosynthetic IPMI from Saccharomyces cerevisiae also catalyzes the hydra-tion of citraconate (27), we predicted that the M. jannaschii IPMI could function in both leucine and isoleucine pathways. Similarly, the M. jannaschii IPMDH homolog could also catalyze the oxidative decarboxylation of ␤-methylmalate to produce 2-oxobutyrate (34).…”

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confidence: 99%

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Enzymology and Evolution of the Pyruvate Pathway to 2-Oxobutyrate in Methanocaldococcus jannaschii

2007

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The archaeon Methanocaldococcus jannaschii uses three different 2-oxoacid elongation pathways, which extend the chain length of precursors in leucine, isoleucine, and coenzyme B biosyntheses. In each of these pathways an aconitase-type hydrolyase catalyzes an hydroxyacid isomerization reaction. The genome sequence of M. jannaschii encodes two homologs of each large and small subunit that forms the hydrolyase, but the genes are not cotranscribed. The genes are more similar to each other than to previously characterized isopropylmalate isomerase or homoaconitase enzyme genes. To identify the functions of these homologs, the four combinations of subunits were heterologously expressed in Escherichia coli, purified, and reconstituted to generate the iron-sulfur center of the holoenzyme. Only the combination of MJ0499 and MJ1277 proteins catalyzed isopropylmalate and citramalate isomerization reactions. This pair also catalyzed hydration half-reactions using citraconate and maleate. Another broad-specificity enzyme, isopropylmalate dehydrogenase (MJ0720), catalyzed the oxidative decarboxylation of ␤-isopropylmalate, ␤-methylmalate, and D-malate. Combined with these results, phylogenetic analysis suggests that the pyruvate pathway to 2-oxobutyrate (an alternative to threonine dehydratase in isoleucine biosynthesis) evolved several times in bacteria and archaea. The enzymes in the isopropylmalate pathway of leucine biosynthesis facilitated the evolution of 2-oxobutyrate biosynthesis through the introduction of a citramalate synthase, either by gene recruitment or gene duplication and functional divergence.

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Section: Discussionmentioning

confidence: 59%

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confidence: 99%

Enzymology and Evolution of the Pyruvate Pathway to 2-Oxobutyrate in Methanocaldococcus jannaschii

2007

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“…Enzyme Assays-Assays for aconitase activity from mammalian IRP1, Leu1, and protein immunoblots were performed as described elsewhere (6,24,34,35).…”

Section: Methodsmentioning

confidence: 99%

Interaction with Cfd1 Increases the Kinetic Lability of FeS on the Nbp35 Scaffold

Pallesen¹,

Solodovnikova²,

Sharma³

et al. 2013

Journal of Biological Chemistry

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Background: A Cfd1 and Nbp35 heterocomplex serves as scaffold for cytosolic iron-sulfur cluster assembly. Results: Deficiency in Cfd1-Nbp35 interaction impaired iron turnover on Nbp35. Conclusion: Cfd1 promotes binding and transfer of labile iron-sulfur cluster on the Nbp35 scaffold. Significance: This is the first insight into the unique roles of these P-loop ATPases in cytosolic iron-sulfur cluster assembly.

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“…Subsequent reactions in this pathway are catalyzed by ␣-IPM isomerase, which is encoded by leuC͞D, and ␤-IPM dehydrogenase, which is encoded by leuB. Biochemical studies of ␣-IPMS have been limited to a few microorganisms, notably Salmonella typhimurium (9), Corynebacterium glutamicum (10), and Saccharomyces cerevisiae (11). The enzyme is dimeric (S. cerevisiae) or tetrameric (S. typhimurium), with a monomer molecular mass of 60-70 kDa, a divalent metal ion dependence, and an alkaline pH optimum.…”

mentioning

confidence: 99%

Crystal structure of LeuA from Mycobacterium tuberculosis , a key enzyme in leucine biosynthesis

Koon

Squire

Baker

2004

Proc. Natl. Acad. Sci. U.S.A.

124

202

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The leucine biosynthetic pathway is essential for the growth of Mycobacterium tuberculosis and is a potential target for the design of new anti-tuberculosis drugs. The crystal structure of ␣-isopropylmalate synthase, which catalyzes the first committed step in this pathway, has been determined by multiwavelength anomalous dispersion methods and refined at 2.0-Å resolution in complex with its substrate ␣-ketoisovalerate. The structure reveals a tightly associated, domain-swapped dimer in which each monomer comprises an (␣͞␤)8 TIM barrel catalytic domain, a helical linker domain, and a regulatory domain of novel fold. Mutational and crystallographic data indicate the latter as the site for leucine feedback inhibition of activity. Domain swapping enables the linker domain of one monomer to sit over the catalytic domain of the other, inserting residues into the active site that may be important in catalysis. The ␣-ketoisovalerate substrate binds to an active site zinc ion, adjacent to a cavity that can accommodate acetyl-CoA. Sequence and structural similarities point to a catalytic mechanism similar to that of malate synthase and an evolutionary relationship with an aldolase that catalyzes the reverse reaction on a similar substrate.

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[53] Isopropylmalate dehydratase from yeast

Cited by 52 publications

References 13 publications

Enzymology and Evolution of the Pyruvate Pathway to 2-Oxobutyrate in Methanocaldococcus jannaschii

Enzymology and Evolution of the Pyruvate Pathway to 2-Oxobutyrate in Methanocaldococcus jannaschii

Interaction with Cfd1 Increases the Kinetic Lability of FeS on the Nbp35 Scaffold

Crystal structure of LeuA from Mycobacterium tuberculosis , a key enzyme in leucine biosynthesis

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