Disease relevance of ADH5

• We examined lifetime and recent (12-24 mo previous) alcohol consumption in relation to risk of lung cancer in a case-control study in western New York. In addition we examined the alcohol dehydrogenase 3 (ADH3) genotype in relation to lung cancer risk; ADH3 is rate limiting in alcohol metabolism and has a functional polymorphism [1].
• CONCLUSIONS: Moderate drinkers who are homozygous for the slow-oxidizing ADH3 allele have higher HDL levels and a substantially decreased risk of myocardial infarction [2].
• METHODS: As part of a population-based study of oral cancer conducted in Puerto Rico, the ADH3 genotypes of 137 patients with histologically confirmed oral cancer and of 146 control subjects (i.e., individuals with no history of oral cancer) were determined by molecular genetic analysis of oral epithelial cell samples [3].
• Furthermore, FDH does not increase cellular folate concentrations by sequestering THF in neuroblastoma nor does it inhibit or regulate de novo purine biosynthesis [4].
• AIM: To investigate if genetic polymorphism in alcohol metabolising enzymes (ADH3, alcohol dehydrogenase 3; ALDH2, aldehyde dehydrogenase 2) is associated with oesophageal multiple dysplasia in head and neck cancer patients [5].

Psychiatry related information on ADH5

• Lung cancer in humans is not associated with lifetime total alcohol consumption or with genetic variation in alcohol dehydrogenase 3 (ADH3) [1].
• Characterized forms suggest that the glutathione-dependent formaldehyde dehydrogenase is the original ancestor, defining a role for the whole protein family in cellular defense mechanisms [6].

High impact information on ADH5

• The ADH3 genotype (gamma1gamma1, gamma1gamma2, or gamma2gamma2) was determined in all subjects [2].
• We confirmed the interaction among the ADH3 genotype, the level of alcohol consumption, and the HDL level in an independent study of postmenopausal women (P=0.02) [2].
• Alcohol dehydrogenase type 3 (ADH3) metabolizes ethanol to acetaldehyde, a carcinogen [3].
• Joint consideration of the DSM-IV diagnosis of alcoholism and the amplitude of the P300 component of the Cz event-related potential significantly increases the evidence for linkage of these traits to a chromosome 4 region near the class I alcohol dehydrogenase locus ADH3 [7].
• The results strongly indicate that Arg-115 in class III alcohol dehydrogenase is a component of the binding site for activating fatty acids and is critical for the binding of S-hydroxymethylglutathione in glutathione-dependent formaldehyde dehydrogenase activity [8].

Chemical compound and disease context of ADH5

• Low FDH expression increased the formyl-THF/THF ratio nearly 10-fold, whereas THF accounted for nearly 50% of total folate in neuroblastoma with high FDH expression [4].
• An air-stable formate dehydrogenase (FDH), an enzyme that catalyzes the oxidation of formate to carbon dioxide, was purified from the sulfate reducing organism Desulfovibrio gigas (D. gigas) NCIB 9332 [9].
• A prospective study of the effect of alcohol consumption and ADH3 genotype on plasma steroid hormone levels and breast cancer risk [10].
• Three different dehydrogenases able to oxidize formaldehyde were found in the Gram-positive methylotroph, Nocardia sp. 239: an NAD-dependent aldehyde dehydrogenase (NA-ADH), and NAD- and factor-dependent formaldehyde dehydrogenase (FD-FDH), and a dye-linked aldehyde dehydrogenase (DL-ADH) [11].
• Two membrane enzymes, d-fructose dehydrogenase from Gluconobacter sp. (FDH) and sarcosine dehydrogenase from Pseudomonas putida (SDH), were for the first time immobilized onto the bilayer membranes of these type of vesicles; and the catalytic activity and enzymatic stability were measured and compared with the enzymes in a vesicle-free solution [12].

Biological context of ADH5

• The human alcohol dehydrogenase (ADH; alcohol:NAD+ oxidoreductase, EC 1.1.1.1) gene family consists of five known loci (ADH1-ADH5), which have been mapped close together on chromosome 4 (4q21-25) [13].
• When its deduced amino acid sequence was compared with those of the class I, class II, and class III ADHs, the proportions of identical amino acids were 56.7%, 55.5%, and 88.7%, respectively, suggesting that the processed pseudogene was derived from an ADH5 gene [14].
• The 5' region of ADH5 contains consensus binding sites for the transcriptional regulatory proteins, Sp1, AP2, LF-A1, NF-1, NF-A2, and NF-E1 [15].
• ADH5 is composed of nine exons and eight introns [15].
• A 1.5-kb upstream fragment from ADH5 was able to drive the transcription of a cat reporter gene at high levels in monkey kidney cells (CV-1) [15].

Anatomical context of ADH5

• An electrophoretic variant for ADH-3 was observed for the enzyme in stomach, kidney, and testis extracts, and activity variation existed for this isozyme in kidney extracts [16].
• With the glutathione-dependent formaldehyde dehydrogenase assay, we found the highest activity in the cytosol of hepatocytes and brain cells (12 and 2.6 mU/mg protein, respectively), but nuclei also exhibited significant activity (1.16 and 2.1 mU/mg protein, respectively) [17].
• In contrast, decay of ADH3 protein was not observed throughout a 4-day period in normal keratinocytes [18].
• In contrast, the ADH3 protein is extremely stable, and consequently is retained during the keratinocyte life span in oral mucosa [18].
• ADH3 mRNA was expressed in basal and parabasal cell layers of oral epithelium, whereas the protein was detected throughout the cell layers [18].

Associations of ADH5 with chemical compounds

• Cloning and characterization of the ADH5 gene encoding human alcohol dehydrogenase 5, formaldehyde dehydrogenase [15].
• N-Heptylformamide inhibited the oxidation of 20-HETE by mouse and human ADH4 but not by ADH3 [19].
• It is inactivated by oxidative metabolism to formate in humans by glutathione-dependent formaldehyde dehydrogenase [20].
• Human glutathione-dependent formaldehyde dehydrogenase plays an important role in the metabolism of glutathione adducts such as S-(hydroxymethyl)glutathione and S-nitrosoglutathione [21].
• Site-directed mutation of this residue to alanine eliminates both fatty acid activation and FDH activity, thus confirming the identity of the modified residue and its function [22].

Regulatory relationships of ADH5

• The ADH5/FDH minimal promoter is potently repressed by the FBI-1 [23].

Other interactions of ADH5

• Here, new restriction fragment length polymorphisms (RFLPs) are described for the genes of two other classes, ADH4 (pi) and ADH5 (chi or formaldehyde dehydrogenase, FDH) [24].
• The human ADH5 and rodent ADH6 seem to be the corresponding enzymes due to their similar behavior [25].
• The 5' region of ADH5 is a CpG island; it is extremely G+C rich and has many CpG doublets [15].
• The alcohol dehydrogenase, class I (ADH2, ADH3) gene cluster can be linked to the alcohol dehydrogenase, class III gene (ADH5) by SacII, NruI, and EagI digests [26].
• Human class III alcohol dehydrogenase (ADH3), also known as glutathione-dependent formaldehyde dehydrogenase, exhibited non-hyperbolic kinetics with ethanol at a near physiological pH 7 [27].

Analytical, diagnostic and therapeutic context of ADH5

• Here we show with PCR amplification of 3'-cDNA ends that the ADH5 gene harbors the "missing" exon [28].
• Sequence analysis of genomic DNA confirmed that the ADH5 gene displays composite internal/terminal exons, which can be differentially processed; i.e., 3'-end generation is a result of competition between polyadenylation and splicing [28].
• This study sought to determine whether an association exists between ADH (ADH1C previously ADH3, ADH1B*2 previously ADH2*2) genotypes, alcohol dependence, drinking history, and liver function tests in the two major ethnic groups of Trinidad and Tobago (TT) [29].
• ADH3 mRNA and protein were further detected in homogenates of oral tissue and various oral cell cultures, including, normal, SV40T antigen-immortalized, and tumor keratinocyte lines [18].
• The immobilization of FDH, GADH, and Cyb2 onto ODTNB-modified gold surfaces has been studied with the quartz crystal microbalance (QCM) [30].

References