Substrate Binding Pocket Structure of Human Aldehyde Dehydrogenases

Yin, Shih‐Jiun; Wang, Mingfang; Han, Chih-Li; Wang, Sung-Ling

doi:10.1007/978-1-4615-1965-2_2

Cited by 20 publications

(9 citation statements)

References 37 publications

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“…The long duration of high blood ethanol concentrations, perhaps reflecting a slow elimination, is most likely attributed to product inhibition of liver ADH activity by acetaldehyde (Peng et al, 1999;Yin et al, 1999). The finding of a slow decline in accumulated blood acetaldehyde is compatible with previous reports that the mutated ALDH2K enzyme exhibits extremely low activity (Farrks et al, 1994;Xiao et al, 1995) and that ALDHl is much less efficient in the oxidation of acetaldehyde (Yin et al, 1995). To accommodate this inborn impairment of acetaldehyde metabolism, this patient had adopted a drinking pattern characterized by slow and prolonged consumption of alcohol that was low in total overall quantity.…”

Section: Discussionsupporting

confidence: 86%

Alcohol Metabolism and Cardiovascular Response in an Alcoholic Patient Homozygous for theALDH2*2Variant Gene Allele

Chen

Peng

et al. 1999

Alcoholism Clin & Exp Res

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105

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The gene status of ALDH2*2/*2 alone can tremendously but not completely (as thought previously) protect against development of alcohol dependence. Individuals carrying the combinatorial genotype of ADH2*2/*2-ALDH2*2/*2 are at the least risk for the disease in East Asians. Physiological tolerance or innate insensitivity to the accumulation of blood acetaldehyde following alcohol ingestion may be crucial for the development of alcoholism in individuals homozygous for ALDH2*2.

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Section: Discussionsupporting

confidence: 86%

Alcohol Metabolism and Cardiovascular Response in an Alcoholic Patient Homozygous for theALDH2*2Variant Gene Allele

Chen

Peng

et al. 1999

Alcoholism Clin & Exp Res

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105

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“…as also reported for class 3 ALDHs (Yin et al, 1995). Presteady-state kinetics showed a burst of 2 mol NADPH/mol dimeric enzyme, indicating that the rate-limiting step must occur after hydride transfer and formation of the acylated intermediate.…”

mentioning

confidence: 59%

Critical Glutamic Acid Residues Affecting the Mechanism and Nucleotide Specificity of Vibrio Harveyi Aldehyde Dehydrogenase

Vedadi

Meighen

1997

European Journal of Biochemistry

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Fatty aldehyde dehydrogenase (ALDH) from the luminescent marine bacterium, Vibrio harveyi, differs from other ALDHs in its unique specificity and high affinity for NADP'. Two glutamic acid residues, Glu253 and Clu377, which are highly conserved in ALDHs, were investigated in the present study. Mutation of Glu253 to Ala decreased the k,,, for ALDH activity by over four orders of magnitude without a significant change in the K,, values for substrates or the ability to interact with nucleotides. Both thioesterase activity and a pre-steady-state burst of NAD(P)H were also eliminated, implicating Glu253 in promoting the nucleophilicity of the cysteine residue(Cys289) involved in forming the thiohemiacetal intermediate in the enzyme mechanism. Mutation of Glu377 to Gln (E377Q mutant) selectively decreased the k,,, for NAD+-dependent ALDH activity (> 10Z-fold) compared to only a 6-fold loss in NADP+-dependent activity without comparable changes to the K,,, values for substrates. Consequently, the E377Q mutant had a very high specificity for NADP+(k,,,/K, > 10' of that for NAD') which was over 20 times higher than that of the wild-type ALDH. Although a pre-steady-state burst of NAD(P)H was eliminated by this mutation, thioesterase activity was completely retained. Using [ 1 -'H]acetaldehyde as a substrate, a significant deuterium isotope effect was observed, implicating Glu377 in the hydride transfer step and not in acylation or release of the acyl group from the cysteine nucleophile. The increase in specificity of the E377Q mutant for NADP' is consistent with a change in the rate-limiting step determining k,,, from nucleotide-dependent NAD(P)H dissociation to hydride transfer. The results provide biochemical evidence that the two highly conserved Glu residues are involved in different functions in the active site of V harveyi ALDH.Keywords: NAD(P)+ : aldehyde dehydrogenase: Vibrio hnweyi ; mutagenesis. Fatty aldehyde dehydrogenase from Mbrio harveyi (Vh.ALDH), a homodimer of I10 kDa, is a NADP+-specific enzyme which catalyzes the oxidation of long-chain aldehydes. The Vh. ALDH gene encodes a protein of 510 amino acids with some characteristics similar to mammalian class 3 ALDHs even though it has low sequence similarity (<25% identity). In particular, Vh. ALDH has a truncated N-terminal and extended Cterminal domain (Vedadi et al., 1995) with a dimeric structure and can utilize both NAD.' as well as NADP ' (Bognar and Meighen, 1978) as can class 3 ALDHs (Lindahl, 1992;Hempel et al., 1993). However, the kLJKm, for Vh. ALDH with NADP' is about 40 times higher than that for NAD' with a low K,, (1.4 pM) for NADP', in contrast to other ALDHs which do not exhibit this unique preference for NADP'. The specificity of the enzyme for long chain aliphatic aldehydes is reflected in a decrease in K , as the chain length of the aldehyde is increased with kLJKrr, being 2.8 X lo4 higher for dodecanal than acetaldehyde and the k,,, values being relatively constant over this rangeCorrespondence fo E.

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“…The upper portion of the substrate-binding tunnel is significantly more hydrophobic in ALDH C relative to Ec-ALDH and likely serves to restrict the polarity of substrates while favoring long-chain aldehydes 15,33,47,48 (Fig. 4, center left panel).…”

Section: Comparative Structural Analysis Of the Substrate-binding Tunnelmentioning

confidence: 95%

Structural and Biochemical Characterization of a Novel Aldehyde Dehydrogenase Encoded by the Benzoate Oxidation Pathway in Burkholderia xenovorans LB400

Bains

Boulanger

2008

Journal of Molecular Biology

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Substrate Binding Pocket Structure of Human Aldehyde Dehydrogenases

Cited by 20 publications

References 37 publications

Alcohol Metabolism and Cardiovascular Response in an Alcoholic Patient Homozygous for theALDH2*2Variant Gene Allele

Alcohol Metabolism and Cardiovascular Response in an Alcoholic Patient Homozygous for theALDH2*2Variant Gene Allele

Critical Glutamic Acid Residues Affecting the Mechanism and Nucleotide Specificity of Vibrio Harveyi Aldehyde Dehydrogenase

Structural and Biochemical Characterization of a Novel Aldehyde Dehydrogenase Encoded by the Benzoate Oxidation Pathway in Burkholderia xenovorans LB400

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