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Structure of the branched-chain keto acid decarboxylase (KdcA) from Lactococcus lactis provides insights into the structural basis for the chemoselective and enantioselective carboligation reaction.

Berthold CL, Gocke D, Wood MD, Leeper FJ, Pohl M, Schneider G
Acta Crystallogr D Biol Crystallogr 63 1217-24 (2007)
Cited: 28 times
EuropePMC logo PMID: 18084069

Abstract

The thiamin diphosphate (ThDP) dependent branched-chain keto acid decarboxylase (KdcA) from Lactococcus lactis catalyzes the decarboxylation of 3-methyl-2-oxobutanoic acid to 3-methylpropanal (isobutyraldehyde) and CO2. The enzyme is also able to catalyze carboligation reactions with an exceptionally broad substrate range, a feature that makes KdcA a potentially valuable biocatalyst for C-C bond formation, in particular for the enzymatic synthesis of diversely substituted 2-hydroxyketones with high enantioselectivity. The crystal structures of recombinant holo-KdcA and of a complex with an inhibitory ThDP analogue mimicking a reaction intermediate have been determined to resolutions of 1.6 and 1.8 A, respectively. KdcA shows the fold and cofactor-protein interactions typical of thiamin-dependent enzymes. In contrast to the tetrameric assembly displayed by most other ThDP-dependent decarboxylases of known structure, KdcA is a homodimer. The crystal structures provide insights into the structural basis of substrate selectivity and stereoselectivity of the enzyme and thus are suitable as a framework for the redesign of the substrate profile in carboligation reactions.

Reviews - 2vbg mentioned but not cited (1)

  1. Protein engineering for metabolic engineering: current and next-generation tools. Marcheschi RJ, Gronenberg LS, Liao JC. Biotechnol J 8 545-555 (2013)

Articles - 2vbg mentioned but not cited (4)

  1. Integrative genomic mining for enzyme function to enable engineering of a non-natural biosynthetic pathway. Mak WS, Tran S, Marcheschi R, Bertolani S, Thompson J, Baker D, Liao JC, Siegel JB. Nat Commun 6 10005 (2015)
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Reviews citing this publication (3)

  1. Thiamin diphosphate in biological chemistry: exploitation of diverse thiamin diphosphate-dependent enzymes for asymmetric chemoenzymatic synthesis. Müller M, Gocke D, Pohl M. FEBS J 276 2894-2904 (2009)
  2. Thiamin diphosphate in biological chemistry: analogues of thiamin diphosphate in studies of enzymes and riboswitches. Agyei-Owusu K, Leeper FJ. FEBS J 276 2905-2916 (2009)
  3. Reaction mechanisms of thiamin diphosphate enzymes: new insights into the role of a conserved glutamate residue. Shaanan B, Chipman DM. FEBS J 276 2447-2453 (2009)

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  2. The Thiamine diphosphate dependent Enzyme Engineering Database: a tool for the systematic analysis of sequence and structure relations. Widmann M, Radloff R, Pleiss J. BMC Biochem 11 9 (2010)
  3. Characterization of a thiamin diphosphate-dependent phenylpyruvate decarboxylase from Saccharomyces cerevisiae. Kneen MM, Stan R, Yep A, Tyler RP, Saehuan C, McLeish MJ. FEBS J 278 1842-1853 (2011)
  4. Rational protein design of ThDP-dependent enzymes-engineering stereoselectivity. Gocke D, Walter L, Gauchenova E, Kolter G, Knoll M, Berthold CL, Schneider G, Pleiss J, Müller M, Pohl M. Chembiochem 9 406-412 (2008)
  5. "η6"-Type anion-π in biomolecular recognition. Chakravarty S, Sheng ZZ, Iverson B, Moore B. FEBS Lett 586 4180-4185 (2012)
  6. On-Demand Production of Flow-Reactor Cartridges by 3D Printing of Thermostable Enzymes. Maier M, Radtke CP, Hubbuch J, Niemeyer CM, Rabe KS. Angew Chem Int Ed Engl 57 5539-5543 (2018)
  7. Validation of a homology model of Mycobacterium tuberculosis DXS: rationalization of observed activities of thiamine derivatives as potent inhibitors of two orthologues of DXS. Masini T, Lacy B, Monjas L, Hawksley D, de Voogd AR, Illarionov B, Iqbal A, Leeper FJ, Fischer M, Kontoyianni M, Hirsch AK. Org Biomol Chem 13 11263-11277 (2015)
  8. Xylose utilization stimulates mitochondrial production of isobutanol and 2-methyl-1-butanol in Saccharomyces cerevisiae. Zhang Y, Lane S, Chen JM, Hammer SK, Luttinger J, Yang L, Jin YS, Avalos JL. Biotechnol Biofuels 12 223 (2019)
  9. A dual conformation of the post-decarboxylation intermediate is associated with distinct enzyme states in mycobacterial KGD (α-ketoglutarate decarboxylase). Wagner T, Barilone N, Alzari PM, Bellinzoni M. Biochem J 457 425-434 (2014)
  10. Oxalyl-CoA Decarboxylase Enables Nucleophilic One-Carbon Extension of Aldehydes to Chiral α-Hydroxy Acids. Burgener S, Cortina NS, Erb TJ. Angew Chem Int Ed Engl 59 5526-5530 (2020)
  11. Saturated mutagenesis of ketoisovalerate decarboxylase V461 enabled specific synthesis of 1-pentanol via the ketoacid elongation cycle. Chen GS, Siao SW, Shen CR. Sci Rep 7 11284 (2017)
  12. A High-Efficiency Artificial Synthetic Pathway for 5-Aminovalerate Production From Biobased L-Lysine in Escherichia coli. Cheng J, Tu W, Luo Z, Gou X, Li Q, Wang D, Zhou J. Front Bioeng Biotechnol 9 633028 (2021)
  13. Branched-chain 2-keto acid decarboxylases derived from Psychrobacter. Wei J, Timler JG, Knutson CM, Barney BM. FEMS Microbiol Lett 346 105-112 (2013)
  14. A Theoretical Study of the Benzoylformate Decarboxylase Reaction Mechanism. Planas F, Sheng X, McLeish MJ, Himo F. Front Chem 6 205 (2018)
  15. Structure-Guided Engineering of α-Keto Acid Decarboxylase for the Production of Higher Alcohols at Elevated Temperature. Sutiono S, Carsten J, Sieber V. ChemSusChem 11 3335-3344 (2018)
  16. Characterisation of a thiamine diphosphate-dependent alpha-keto acid decarboxylase from Proteus mirabilis JN458. Wang B, Bai Y, Fan T, Zheng X, Cai Y. Food Chem 232 19-24 (2017)
  17. A short-chain acyl-CoA synthetase that supports branched-chain fatty acid synthesis in Staphylococcus aureus. Whaley SG, Frank MW, Rock CO. J Biol Chem 299 103036 (2023)
  18. Machine learning discovery of missing links that mediate alternative branches to plant alkaloids. Vavricka CJ, Takahashi S, Watanabe N, Takenaka M, Matsuda M, Yoshida T, Suzuki R, Kiyota H, Li J, Minami H, Ishii J, Tsuge K, Araki M, Kondo A, Hasunuma T. Nat Commun 13 1405 (2022)
  19. Systematic Functional Analysis of Active-Site Residues in l-Threonine Dehydrogenase from Thermoplasma volcanium. Desjardins M, Mak WS, O'Brien TE, Carlin DA, Tantillo DJ, Siegel JB. ACS Omega 2 3308-3314 (2017)
  20. Computational evaluation of factors governing catalytic 2-keto acid decarboxylation. Wu D, Yue D, You F, Broadbelt LJ. J Mol Model 20 2310 (2014)


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