1u3u › Citations

Structure of three class I human alcohol dehydrogenases complexed with isoenzyme specific formamide inhibitors.

Gibbons BJ, Hurley TD
Biochemistry 43 12555-62 (2004)
Related entries: 1u3t, 1u3v, 1u3w

Cited: 17 times
EuropePMC logo PMID: 15449945

Abstract

Formamides are aldehyde analogues that have demonstrated potent and selective inhibition of human alcohol dehydrogenase isoenzymes. The alphaalpha, beta(1)beta(1), gamma(2)gamma(2), and sigmasigma isoforms have all been found to be strongly inhibited by substituted formamides. In this paper, the structure of the alphaalpha isoform of human alcohol dehydrogenase complexed with N-cyclopentyl-N-cyclobutylformamide was determined by X-ray crystallography to 2.5 A resolution, the beta(1)beta(1) isoform of human alcohol dehydrogenase complexed with N-benzylformamide and with N-heptylformamide was determined to 1.6 and 1.65 A resolution, respectively, and the structure of the gamma(2)gamma(2) isoform complexed with N-1-methylheptylformamide was determined to 1.45 A resolution. These structures provide the first substrate-level view of the local structural differences that give rise to the individual substrate preferences shown by these highly related isoenzymes. Consistent with previous work, the carbonyl oxygen of the inhibitors interacts directly with the catalytic zinc and the hydroxyl group of Thr48 (Ser48 for gamma(2)gamma(2)) of the enzyme. The benzene ring of N-benzylformamide and the carbon chains of N-heptylformamide and N-1-methylheptylformamide interact with the sides of the hydrophobic substrate pocket whose size and shape is dictated by residue exchanges between the beta(1)beta(1) and gamma(2)gamma(2) isoenzymes. In particular, the exchange of Ser for Thr at position 48 and the exchange of Val for Leu at position 141 in the gamma(2)gamma(2) isoenzyme create an environment with stereoselectivity for the R-enantiomer of the branched N-1-methylheptylformamide inhibitor in this isoenzyme. The primary feature of the alphaalpha isoform is the Ala for Phe93 exchange that enlarges the active site near the catalytic zinc and creates the specificity for the branched N-cyclopentyl-N-cyclobutylformamide inhibitor, which shows the greatest selectivity for this unique isoenzyme of any of the formamide inhibitors.

Articles - 1u3u mentioned but not cited (5)

  1. Atomic-resolution structures of horse liver alcohol dehydrogenase with NAD(+) and fluoroalcohols define strained Michaelis complexes. Plapp BV, Ramaswamy S. Biochemistry 51 4035-4048 (2012)
  2. Mapping small molecule binding data to structural domains. Kruger FA, Rostom R, Overington JP. BMC Bioinformatics 13 Suppl 17 S11 (2012)
  3. Unexpected roles for ADH1 and SORD in catalyzing the final step of erythritol biosynthesis. Schlicker L, Szebenyi DME, Ortiz SR, Heinz A, Hiller K, Field MS. J Biol Chem 294 16095-16108 (2019)
  4. Functional Classification of Super-Large Families of Enzymes Based on Substrate Binding Pocket Residues for Biocatalysis and Enzyme Engineering Applications. Sirota FL, Maurer-Stroh S, Li Z, Eisenhaber F, Eisenhaber B. Front Bioeng Biotechnol 9 701120 (2021)
  5. Visible light-induced photoredox catalyzed C-N coupling of amides with alcohols. Tivari S, Singh PK, Singh PP, Srivastava V. RSC Adv 12 35221-35226 (2022)


Reviews citing this publication (3)

  1. Targeting Metalloenzymes for Therapeutic Intervention. Chen AY, Adamek RN, Dick BL, Credille CV, Morrison CN, Cohen SM. Chem Rev 119 1323-1455 (2019)
  2. Conformational changes and catalysis by alcohol dehydrogenase. Plapp BV. Arch Biochem Biophys 493 3-12 (2010)
  3. The Role of Alcohol Dehydrogenase in Drug Metabolism: Beyond Ethanol Oxidation. Di L, Balesano A, Jordan S, Shi SM. AAPS J 23 20 (2021)

Articles citing this publication (9)

  1. Structural Basis for Cyclopropanation by a Unique Enoyl-Acyl Carrier Protein Reductase. Khare D, Hale WA, Tripathi A, Gu L, Sherman DH, Gerwick WH, Håkansson K, Smith JL. Structure 23 2213-2223 (2015)
  2. Unconserved substrate-binding sites direct the stereoselectivity of medium-chain alcohol dehydrogenase. Wang S, Nie Y, Xu Y, Zhang R, Ko TP, Huang CH, Chan HC, Guo RT, Xiao R. Chem Commun (Camb) 50 7770-7772 (2014)
  3. Effects of cavities at the nicotinamide binding site of liver alcohol dehydrogenase on structure, dynamics and catalysis. Yahashiri A, Rubach JK, Plapp BV. Biochemistry 53 881-894 (2014)
  4. Horse Liver Alcohol Dehydrogenase: Zinc Coordination and Catalysis. Plapp BV, Savarimuthu BR, Ferraro DJ, Rubach JK, Brown EN, Ramaswamy S. Biochemistry 56 3632-3646 (2017)
  5. Role of tryptophan 95 in substrate specificity and structural stability of Sulfolobus solfataricus alcohol dehydrogenase. Pennacchio A, Esposito L, Zagari A, Rossi M, Raia CA. Extremophiles 13 751-761 (2009)
  6. The natural history of class I primate alcohol dehydrogenases includes gene duplication, gene loss, and gene conversion. Carrigan MA, Uryasev O, Davis RP, Zhai L, Hurley TD, Benner SA. PLoS One 7 e41175 (2012)
  7. Inversion of substrate stereoselectivity of horse liver alcohol dehydrogenase by substitutions of Ser-48 and Phe-93. Kim K, Plapp BV. Chem Biol Interact 276 77-87 (2017)
  8. Computational studies of human class V alcohol dehydrogenase - the odd sibling. Östberg LJ, Persson B, Höög JO. BMC Biochem 17 16 (2016)
  9. Systematic in silico Evaluation of Leishmania spp. Proteomes for Drug Discovery. Dos Santos Vasconcelos CR, Rezende AM. Front Chem 9 607139 (2021)


Quick links