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Mechanism of substrate recognition and insight into feedback inhibition of homocitrate synthase from Thermus thermophilus.

Okada T, Tomita T, Wulandari AP, Kuzuyama T, Nishiyama M
J Biol Chem 285 4195-4205 (2010)
Related entries: 2ztj, 2ztk, 2zyf

Cited: 20 times
EuropePMC logo PMID: 19996101

Abstract

Homocitrate synthase (HCS) catalyzes aldol-type condensation of acetyl coenzyme A (acetyl-CoA) and alpha-ketoglutarate (alpha-KG) to synthesize homocitrate (HC), which is the first and committed step in the lysine biosynthetic pathway through alpha-aminoadipate. As known in most enzymes catalyzing the first reactions in amino acid biosynthetic pathways, HCS is regulated via feedback inhibition by the end product, lysine. Here, we determined the crystal structures of HCS from Thermus thermophilus complexed with alpha-KG, HC, or lysine. In the HC complex, the C1-carboxyl group of HC, which is derived from acetyl-CoA, is hydrogen-bonded with His-292* from another subunit (indicated by the asterisk), indicating direct involvement of this residue in the catalytic mechanism of HCS. The crystal structure of HCS complexed with lysine showed that lysine is bound to the active site with rearrangement of amino acid residues in the substrate-binding site, which accounts for the competitive inhibition by lysine with alpha-KG. Comparison between the structures suggests that His-72, which is conserved in lysine-sensitive HCSs and binds the C5-carboxyl group of alpha-KG, serves as a switch for the conformational change. Replacement of His-72 by leucine made HCS resistant to lysine inhibition, demonstrating the regulatory role of this conserved residue.

Reviews - 3a9i mentioned but not cited (1)

  1. Insight into de-regulation of amino acid feedback inhibition: a focus on structure analysis method. Naz S, Liu P, Farooq U, Ma H. Microb Cell Fact 22 161 (2023)

Articles - 3a9i mentioned but not cited (2)

  1. Mechanism of substrate recognition and insight into feedback inhibition of homocitrate synthase from Thermus thermophilus. Okada T, Tomita T, Wulandari AP, Kuzuyama T, Nishiyama M. J Biol Chem 285 4195-4205 (2010)
  2. Kinetic and chemical mechanisms of homocitrate synthase from Thermus thermophilus. Kumar VP, West AH, Cook PF. J Biol Chem 286 29428-29439 (2011)


Reviews citing this publication (3)

  1. The Spectroscopy of Nitrogenases. Van Stappen C, Decamps L, Cutsail GE, Bjornsson R, Henthorn JT, Birrell JA, DeBeer S. Chem Rev 120 5005-5081 (2020)
  2. Convergent strategies in biosynthesis. Dairi T, Kuzuyama T, Nishiyama M, Fujii I. Nat Prod Rep 28 1054-1086 (2011)
  3. Structure, function, and regulation of enzymes involved in amino acid metabolism of bacteria and archaea. Tomita T. Biosci Biotechnol Biochem 81 2050-2061 (2017)

Articles citing this publication (14)

  1. Structural basis for L-lysine feedback inhibition of homocitrate synthase. Bulfer SL, Scott EM, Pillus L, Trievel RC. J Biol Chem 285 10446-10453 (2010)
  2. Molecular Basis of the Evolution of Methylthioalkylmalate Synthase and the Diversity of Methionine-Derived Glucosinolates. Kumar R, Lee SG, Augustine R, Reichelt M, Vassão DG, Palavalli MH, Allen A, Gershenzon J, Jez JM, Bisht NC. Plant Cell 31 1633-1647 (2019)
  3. Application of a high-throughput fluorescent acetyltransferase assay to identify inhibitors of homocitrate synthase. Bulfer SL, McQuade TJ, Larsen MJ, Trievel RC. Anal Biochem 410 133-140 (2011)
  4. Changing substrate specificity and iteration of amino acid chain elongation in glucosinolate biosynthesis through targeted mutagenesis of Arabidopsis methylthioalkylmalate synthase 1. Petersen A, Hansen LG, Mirza N, Crocoll C, Mirza O, Halkier BA. Biosci Rep 39 BSR20190446 (2019)
  5. Mechanistic and bioinformatic investigation of a conserved active site helix in α-isopropylmalate synthase from Mycobacterium tuberculosis, a member of the DRE-TIM metallolyase superfamily. Casey AK, Hicks MA, Johnson JL, Babbitt PC, Frantom PA. Biochemistry 53 2915-2925 (2014)
  6. The Lys20 homocitrate synthase isoform exerts most of the flux control over the lysine synthesis pathway in Saccharomyces cerevisiae. Quezada H, Marín-Hernández A, Aguilar D, López G, Gallardo-Pérez JC, Jasso-Chávez R, González A, Saavedra E, Moreno-Sánchez R. Mol Microbiol 82 578-590 (2011)
  7. Biochemical effects of venlafaxine on astrocytes as revealed by 1H NMR-based metabolic profiling. Sun L, Fang L, Lian B, Xia JJ, Zhou CJ, Wang L, Mao Q, Wang XF, Gong X, Liang ZH, Bai SJ, Liao L, Wu Y, Xie P. Mol Biosyst 13 338-349 (2017)
  8. New Therapeutic Candidates for the Treatment of Malassezia pachydermatis -Associated Infections. Sastoque A, Triana S, Ehemann K, Suarez L, Restrepo S, Wösten H, de Cock H, Fernández-Niño M, González Barrios AF, Celis Ramírez AM. Sci Rep 10 4860 (2020)
  9. High-Level Production of Lysine in the Yeast Saccharomyces cerevisiae by Rational Design of Homocitrate Synthase. Isogai S, Matsushita T, Imanishi H, Koonthongkaew J, Toyokawa Y, Nishimura A, Yi X, Kazlauskas R, Takagi H. Appl Environ Microbiol 87 e0060021 (2021)
  10. Glucosinolate biosynthesis: role of MAM synthase and its perspectives. Das B. Biosci Rep 41 BSR20211634 (2021)
  11. Modifying the determinants of α-ketoacid substrate selectivity in mycobacterium tuberculosis α-isopropylmalate synthase. Hunter MF, Parker EJ. FEBS Lett 588 1603-1607 (2014)
  12. Two ATP-binding cassette transporters involved in (S)-2-aminoethyl-cysteine uptake in thermus thermophilus. Kanemaru Y, Hasebe F, Tomita T, Kuzuyama T, Nishiyama M. J Bacteriol 195 3845-3853 (2013)
  13. Conformational interdomain flexibility in a bacterial α-isopropylmalate synthase is necessary for leucine biosynthesis. Bai Y, Jiao W, Vörster J, Parker EJ. J Biol Chem 299 102789 (2023)
  14. Novel protein from larval sponge cells, ilborin, is related to energy turnover and calcium binding and is conserved among marine invertebrates. Borisenko I, Daugavet M, Ereskovsky A, Lavrov A, Podgornaya O. Open Biol 12 210336 (2022)


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