Skip to main content
NCBI home page
Protein Science : A Publication of the Protein Society logoLink to Protein Science : A Publication of the Protein Society
. 1993 Nov;2(11):1890–1900. doi: 10.1002/pro.5560021111

Aldehyde dehydrogenases: widespread structural and functional diversity within a shared framework.

J Hempel 1, H Nicholas 1, R Lindahl 1
PMCID: PMC2142294  PMID: 8268800

Abstract

Sequences of 16 NAD and/or NADP-linked aldehyde oxidoreductases are aligned, including representative examples of all aldehyde dehydrogenase forms with wide substrate preferences as well as additional types with distinct specificities for certain metabolic aldehyde intermediates, particularly semialdehydes, yielding pairwise identities from 15 to 83%. Eleven of 23 invariant residues are glycine and three are proline, indicating evolutionary restraint against alteration of peptide chain-bending points. Additionally, another 66 positions show high conservation of residue type, mostly hydrophobic residues. Ten of these occur in predicted beta-strands, suggesting important interior-packing interactions. A single invariant cysteine residue is found, further supporting its catalytic role. A previously identified essential glutamic acid residue is conserved in all but methyl malonyl semialdehyde dehydrogenase, which may relate to formation by that enzyme of a CoA ester as a product rather than a free carboxylate species. Earlier, similarity to a GXGXXG segment expected in the NAD-binding site was noted from alignments with fewer sequences. The same region continues to be indicated, although now only the first glycine residue is strictly conserved and the second (usually threonine) is not present at all, suggesting greater variance in coenzyme-binding interactions.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abriola D. P., Fields R., Stein S., MacKerell A. D., Jr, Pietruszko R. Active site of human liver aldehyde dehydrogenase. Biochemistry. 1987 Sep 8;26(18):5679–5684. doi: 10.1021/bi00392a015. [DOI] [PubMed] [Google Scholar]
  2. Bernstein F. C., Koetzle T. F., Williams G. J., Meyer E. F., Jr, Brice M. D., Rodgers J. R., Kennard O., Shimanouchi T., Tasumi M. The Protein Data Bank: a computer-based archival file for macromolecular structures. J Mol Biol. 1977 May 25;112(3):535–542. doi: 10.1016/s0022-2836(77)80200-3. [DOI] [PubMed] [Google Scholar]
  3. Borrás T., Persson B., Jörnvall H. Eye lens zeta-crystallin relationships to the family of "long-chain" alcohol/polyol dehydrogenases. Protein trimming and conservation of stable parts. Biochemistry. 1989 Jul 25;28(15):6133–6139. doi: 10.1021/bi00441a001. [DOI] [PubMed] [Google Scholar]
  4. Chou P. Y., Fasman G. D. Empirical predictions of protein conformation. Annu Rev Biochem. 1978;47:251–276. doi: 10.1146/annurev.bi.47.070178.001343. [DOI] [PubMed] [Google Scholar]
  5. Clark S. P. MALIGNED: a multiple sequence alignment editor. Comput Appl Biosci. 1992 Dec;8(6):535–538. doi: 10.1093/bioinformatics/8.6.535. [DOI] [PubMed] [Google Scholar]
  6. Cook R. J., Lloyd R. S., Wagner C. Isolation and characterization of cDNA clones for rat liver 10-formyltetrahydrofolate dehydrogenase. J Biol Chem. 1991 Mar 15;266(8):4965–4973. [PubMed] [Google Scholar]
  7. Cooper D. L., Baptist E. W. Degenerate oligonucleotide sequence-directed cross-species PCR cloning of the BCP 54/ALDH 3 cDNA: priming from inverted repeats and formation of tandem primer arrays. PCR Methods Appl. 1991 Aug;1(1):57–62. doi: 10.1101/gr.1.1.57. [DOI] [PubMed] [Google Scholar]
  8. Dayhoff M. O., Barker W. C., Hunt L. T. Establishing homologies in protein sequences. Methods Enzymol. 1983;91:524–545. doi: 10.1016/s0076-6879(83)91049-2. [DOI] [PubMed] [Google Scholar]
  9. Dunn T. J., Koleske A. J., Lindahl R., Pitot H. C. Phenobarbital-inducible aldehyde dehydrogenase in the rat. cDNA sequence and regulation of the mRNA by phenobarbital in responsive rats. J Biol Chem. 1989 Aug 5;264(22):13057–13065. [PubMed] [Google Scholar]
  10. Eklund H., Nordström B., Zeppezauer E., Söderlund G., Ohlsson I., Boiwe T., Söderberg B. O., Tapia O., Brändén C. I., Akeson A. Three-dimensional structure of horse liver alcohol dehydrogenase at 2-4 A resolution. J Mol Biol. 1976 Mar 25;102(1):27–59. doi: 10.1016/0022-2836(76)90072-3. [DOI] [PubMed] [Google Scholar]
  11. Fitch W. M., Margoliash E. Construction of phylogenetic trees. Science. 1967 Jan 20;155(3760):279–284. doi: 10.1126/science.155.3760.279. [DOI] [PubMed] [Google Scholar]
  12. George D. G., Barker W. C., Hunt L. T. The protein identification resource (PIR). Nucleic Acids Res. 1986 Jan 10;14(1):11–15. doi: 10.1093/nar/14.1.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Heim R., Strehler E. E. Cloning an Escherichia coli gene encoding a protein remarkably similar to mammalian aldehyde dehydrogenases. Gene. 1991 Mar 1;99(1):15–23. doi: 10.1016/0378-1119(91)90028-a. [DOI] [PubMed] [Google Scholar]
  14. Hempel J., Harper K., Lindahl R. Inducible (class 3) aldehyde dehydrogenase from rat hepatocellular carcinoma and 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated liver: distant relationship to the class 1 and 2 enzymes from mammalian liver cytosol/mitochondria. Biochemistry. 1989 Feb 7;28(3):1160–1167. doi: 10.1021/bi00429a034. [DOI] [PubMed] [Google Scholar]
  15. Hempel J., Kaiser R., Jörnvall H. Mitochondrial aldehyde dehydrogenase from human liver. Primary structure, differences in relation to the cytosolic enzyme, and functional correlations. Eur J Biochem. 1985 Nov 15;153(1):13–28. doi: 10.1111/j.1432-1033.1985.tb09260.x. [DOI] [PubMed] [Google Scholar]
  16. Hempel J., Nicholas H., Jörnvall H. Thiol proteases and aldehyde dehydrogenases: evolution from a common thiolesterase precursor? Proteins. 1991;11(3):176–183. doi: 10.1002/prot.340110303. [DOI] [PubMed] [Google Scholar]
  17. Hempel J., Pietruszko R., Fietzek P., Jörnvall H. Identification of a segment containing a reactive cysteine residue in human liver cytoplasmic aldehyde dehydrogenase (isoenzyme E1). Biochemistry. 1982 Dec 21;21(26):6834–6838. doi: 10.1021/bi00269a032. [DOI] [PubMed] [Google Scholar]
  18. Hempel J., von Bahr-Lindström H., Jörnvall H. Aldehyde dehydrogenase from human liver. Primary structure of the cytoplasmic isoenzyme. Eur J Biochem. 1984 May 15;141(1):21–35. doi: 10.1111/j.1432-1033.1984.tb08150.x. [DOI] [PubMed] [Google Scholar]
  19. Hsu L. C., Chang W. C. Cloning and characterization of a new functional human aldehyde dehydrogenase gene. J Biol Chem. 1991 Jul 5;266(19):12257–12265. [PubMed] [Google Scholar]
  20. Johansson J., von Bahr-Lindström H., Jeck R., Woenckhaus C., Jörnvall H. Mitochondrial aldehyde dehydrogenase from horse liver. Correlations of the same species variants for both the cytosolic and the mitochondrial forms of an enzyme. Eur J Biochem. 1988 Mar 15;172(3):527–533. doi: 10.1111/j.1432-1033.1988.tb13920.x. [DOI] [PubMed] [Google Scholar]
  21. Jörnvall H. Differences between alcohol dehydrogenases. Structural properties and evolutionary aspects. Eur J Biochem. 1977 Feb;72(3):443–452. doi: 10.1111/j.1432-1033.1977.tb11268.x. [DOI] [PubMed] [Google Scholar]
  22. Kedishvili N. Y., Popov K. M., Rougraff P. M., Zhao Y., Crabb D. W., Harris R. A. CoA-dependent methylmalonate-semialdehyde dehydrogenase, a unique member of the aldehyde dehydrogenase superfamily. cDNA cloning, evolutionary relationships, and tissue distribution. J Biol Chem. 1992 Sep 25;267(27):19724–19729. [PubMed] [Google Scholar]
  23. Kok M., Oldenhuis R., van der Linden M. P., Meulenberg C. H., Kingma J., Witholt B. The Pseudomonas oleovorans alkBAC operon encodes two structurally related rubredoxins and an aldehyde dehydrogenase. J Biol Chem. 1989 Apr 5;264(10):5442–5451. [PubMed] [Google Scholar]
  24. Lesk A. M., Chothia C. How different amino acid sequences determine similar protein structures: the structure and evolutionary dynamics of the globins. J Mol Biol. 1980 Jan 25;136(3):225–270. doi: 10.1016/0022-2836(80)90373-3. [DOI] [PubMed] [Google Scholar]
  25. Miyauchi K., Masaki R., Taketani S., Yamamoto A., Akayama M., Tashiro Y. Molecular cloning, sequencing, and expression of cDNA for rat liver microsomal aldehyde dehydrogenase. J Biol Chem. 1991 Oct 15;266(29):19536–19542. [PubMed] [Google Scholar]
  26. Nordlund I., Shingler V. Nucleotide sequences of the meta-cleavage pathway enzymes 2-hydroxymuconic semialdehyde dehydrogenase and 2-hydroxymuconic semialdehyde hydrolase from Pseudomonas CF600. Biochim Biophys Acta. 1990 Jun 21;1049(2):227–230. doi: 10.1016/0167-4781(90)90046-5. [DOI] [PubMed] [Google Scholar]
  27. Persson B., Krook M., Jörnvall H. Characteristics of short-chain alcohol dehydrogenases and related enzymes. Eur J Biochem. 1991 Sep 1;200(2):537–543. doi: 10.1111/j.1432-1033.1991.tb16215.x. [DOI] [PubMed] [Google Scholar]
  28. Pickett M., Gwynne D. I., Buxton F. P., Elliott R., Davies R. W., Lockington R. A., Scazzocchio C., Sealy-Lewis H. M. Cloning and characterization of the aldA gene of Aspergillus nidulans. Gene. 1987;51(2-3):217–226. doi: 10.1016/0378-1119(87)90310-6. [DOI] [PubMed] [Google Scholar]
  29. Pietruszko R., Blatter E., Abriola D. P., Prestwich G. Localization of cysteine 302 at the active site of aldehyde dehydrogenase. Adv Exp Med Biol. 1991;284:19–30. doi: 10.1007/978-1-4684-5901-2_4. [DOI] [PubMed] [Google Scholar]
  30. Rondeau J. M., Tête-Favier F., Podjarny A., Reymann J. M., Barth P., Biellmann J. F., Moras D. Novel NADPH-binding domain revealed by the crystal structure of aldose reductase. Nature. 1992 Jan 30;355(6359):469–472. doi: 10.1038/355469a0. [DOI] [PubMed] [Google Scholar]
  31. Rose J. P., Hempel J., Kuo I., Lindahl R., Wang B. C. Preliminary crystallographic analysis of class 3 rat liver aldehyde dehydrogenase. Proteins. 1990;8(4):305–308. doi: 10.1002/prot.340080404. [DOI] [PubMed] [Google Scholar]
  32. Rossmann M. G., Moras D., Olsen K. W. Chemical and biological evolution of nucleotide-binding protein. Nature. 1974 Jul 19;250(463):194–199. doi: 10.1038/250194a0. [DOI] [PubMed] [Google Scholar]
  33. Saigal D., Cunningham S. J., Farrés J., Weiner H. Molecular cloning of the mitochondrial aldehyde dehydrogenase gene of Saccharomyces cerevisiae by genetic complementation. J Bacteriol. 1991 May;173(10):3199–3208. doi: 10.1128/jb.173.10.3199-3208.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Takahashi K., Weiner H., Filmer D. L. Effects of pH on horse liver aldehyde dehydrogenase: alterations in metal ion activation, number of functioning active sites, and hydrolysis of the acyl intermediate. Biochemistry. 1981 Oct 13;20(21):6225–6230. doi: 10.1021/bi00524a049. [DOI] [PubMed] [Google Scholar]
  35. von Bahr-Lindström H., Hempel J., Jörnvall H. The cytoplasmic isoenzyme of horse liver aldehyde dehydrogenase. Relationship to the corresponding human isoenzyme. Eur J Biochem. 1984 May 15;141(1):37–42. doi: 10.1111/j.1432-1033.1984.tb08152.x. [DOI] [PubMed] [Google Scholar]
  36. von Bahr-Lindström H., Jeck R., Woenckhaus C., Sohn S., Hempel J., Jörnvall H. Characterization of the coenzyme binding site of liver aldehyde dehydrogenase: differential reactivity of coenzyme analogues. Biochemistry. 1985 Oct 8;24(21):5847–5851. doi: 10.1021/bi00342a023. [DOI] [PubMed] [Google Scholar]

Articles from Protein Science : A Publication of the Protein Society are provided here courtesy of The Protein Society

RESOURCES