RGD Reference Report - Molecular basis for differential substrate specificity in class IV alcohol dehydrogenases: a conserved function in retinoid metabolism but not in ethanol oxidation. - Rat Genome Database

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Molecular basis for differential substrate specificity in class IV alcohol dehydrogenases: a conserved function in retinoid metabolism but not in ethanol oxidation.

Authors: Crosas, B  Allali-Hassani, A  Martinez, SE  Martras, S  Persson, B  Jornvall, H  Pares, X  Farres, J 
Citation: Crosas B, etal., J Biol Chem 2000 Aug 18;275(33):25180-7.
RGD ID: 631904
Pubmed: PMID:10829036   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M910040199   (Journal Full-text)

Mammalian class IV alcohol dehydrogenase enzymes are characteristic of epithelial tissues, exhibit moderate to high K(m) values for ethanol, and are very active in retinol oxidation. The human enzyme shows a K(m) value for ethanol which is 2 orders of magnitude lower than that of rat class IV. The uniquely significant difference in the substrate-binding pocket between the two enzymes appears to be at position 294, Val in the human enzyme and Ala in the rat enzyme. Moreover, a deletion at position 117 (Gly in class I) has been pointed out as probably responsible for class IV specificity toward retinoids. With the aim of establishing the role of these residues, we have studied the kinetics of the recombinant human and rat wild-type enzymes, the human G117ins and V294A mutants, and the rat A294V mutant toward aliphatic alcohols and retinoids. 9-cis-Retinol was the best retinoid substrate for both human and rat class IV, strongly supporting a role of class IV in the generation of 9-cis-retinoic acid. In contrast, 13-cis retinoids were not substrates. The G117ins mutant showed a decreased catalytic efficiency toward retinoids and toward three-carbon and longer primary aliphatic alcohols, a behavior that resembles that of the human class I enzyme, which has Gly(117). The K(m) values for ethanol dramatically changed in the 294 mutants, where the human V294A mutant showed a 280-fold increase, and the rat A294V mutant a 50-fold decrease, compared with those of the respective wild-type enzymes. This demonstrates that the Val/Ala exchange at position 294 is mostly responsible for the kinetic differences with ethanol between the human and rat class IV. In contrast, the kinetics toward retinoids was only slightly affected by the mutations at position 294, compatible with a more conserved function of mammalian class IV alcohol dehydrogenase in retinoid metabolism.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Adh7Ratethanol metabolic process  IDA  RGD 
Adh7Ratretinoid metabolic process  TAS  RGD 
Adh7Ratretinol metabolic process  IDA  RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Adh7Ratalcohol dehydrogenase (NAD+) activity  IDA  RGD 
Adh7Ratethanol binding  IDA  RGD 
Adh7RatNAD binding  IDA  RGD 
Adh7Ratretinol binding  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Adh7  (alcohol dehydrogenase 7 (class IV), mu or sigma polypeptide)


Additional Information