Identification of a novel cytosolic aldehyde dehydrogenase allele, ALDHIAI*4
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Identification of a novel cytosolic aldehyde dehydrogenase allele, ALDH1A1*4 Shelley M. Moore,1* Tiebing Liang,2 Tamara J. Graves,2 Kevin M. McCall,2 Lucinda G. Carr2 and Cindy L. Ehlers3 1
Pharmacology Unit, Department of Paraclinical Sciences, Faculty of Medical Sciences, The University of the West Indies, St. Augustine, Trinidad and Tobago 2 Indiana University School of Medicine, 975 W. Walnut Street, IB424, Indianapolis, IN 46202-5121, USA 3 Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, 10550 N. Torrey Pines Rd, SP30-1501, La Jolla, CA 92037, USA *Correspondence to: Tel: þ1 868 663 8613; E-mail: [email protected] Date received (in revised form): 24th February 2009
Abstract This paper reports the identification of a novel cytosolic aldehyde dehydrogenase 1 (ALDH1A1) allele. One hundred and sixty-two Indo-Trinidadian and 85 Afro-Trinidadian individuals were genotyped. A novel ALDH1A1 allele, ALDH1A1*4, was identified in an Indo-Trinidadian alcoholic with an A inserted at position –554 relative to the translational start site, þ1. It was concluded that a wider cross-section of individuals needs to be evaluated in order to determine the representative frequency of the allele, and to see if it is associated with risk of alcoholism. Keywords: ALDH1A1, base pair, polymorphism, Trinidad and Tobago
Introduction The human cytosolic enzyme aldehyde dehydrogenase 1 (ALDH1A1) functions mainly in acetaldehyde and neurotransmitter metabolism. It is also reported to play a major role in the production of retinoic acid, which is important for gene expression and tissue differentiation, and also in cyclophosphamide detoxification.1 – 3 It is found in various tissues, including the central nervous system (CNS),4 with highest levels in the liver.2 Research has implicated the enzyme in the development of alcohol dependence and other alcohol-use disorders, alcohol-induced flushing and sensitivity to alcohol.3,5,6 Normal ALDH1A1, is tetrameric and predominantly of cytosolic origin. This enzyme has a relatively high Km (50–100 mM),7,8 which is far greater than recorded physiological concentrations
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(0.4–2.5 mM).9 – 12 In addition, this enzyme has low catalytic efficiency (Kcat/Km)13 for acetaldehyde metabolism and hence exhibits its importance in ethanol elimination. Research into ALDH1A1 kinetics with respect to various neurotransmitter aldehydes reveals a Km of 2.4 mM for 5-hydroxyindole acetaldehyde and a Km of 0.4 mM and 1.5 mM for 3,4-dihydroxyphenylacetaldehyde and phenylacetaldehyde, respectively, and near equivalent Kcat values for these substrates.14 ALDH1A1 has also displayed a Km of 0.06 mM in retinaldehyde metabolism, with the Kcat value equivalent to the value in acetaldehyde metabolism.8 These functions are so important that some researchers believe that this enzyme is essential for life, and this belief is supported by the evidence that no individual has yet been identified with a total absence of ALDH1A1 catalytic activity.15
# HENRY STEWART PUBLICATIONS 1479 –7364.
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