Human class IV alcohol dehydrogenase: kinetic mechanism, functional roles and medical relevance

Yin, Shih‐Jiun; Chou, Chu-Fang; Lai, Ching‐Long; Lee, Shou-Lun; Han, Chih-Li

doi:10.1016/s0009-2797(02)00167-9

Cited by 49 publications

(38 citation statements)

References 48 publications

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“…The heterologously expressed proteins were isolated following the procedures of Niederhut et al (74). The activity and kinetic parameters were characterized by measuring the formation of NADH using various alcohols as substrates as in Yin et al (75), with the exception that BSA was included in the assays at 0.2 mg/mL The kinetic values we obtained for human ADH4 were similar to those reported in the literature by others (76). Statistical significance was determined using a modification of a twotailed Student t test that does not assume equal variances between the two populations being tested (also known as Welch's t test).…”

Section: Methodssupporting

confidence: 67%

See 1 more Smart Citation

Hominids adapted to metabolize ethanol long before human-directed fermentation

Carrigan

Uryasev

Frye

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

126

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Paleogenetics is an emerging field that resurrects ancestral proteins from now-extinct organisms to test, in the laboratory, models of protein function based on natural history and Darwinian evolution. Here, we resurrect digestive alcohol dehydrogenases (ADH4) from our primate ancestors to explore the history of primate-ethanol interactions. The evolving catalytic properties of these resurrected enzymes show that our ape ancestors gained a digestive dehydrogenase enzyme capable of metabolizing ethanol near the time that they began using the forest floor, about 10 million y ago. The ADH4 enzyme in our more ancient and arboreal ancestors did not efficiently oxidize ethanol. This change suggests that exposure to dietary sources of ethanol increased in hominids during the early stages of our adaptation to a terrestrial lifestyle. Because fruit collected from the forest floor is expected to contain higher concentrations of fermenting yeast and ethanol than similar fruits hanging on trees, this transition may also be the first time our ancestors were exposed to (and adapted to) substantial amounts of dietary ethanol.experimental paleogenetics | alcohol dehydrogenase | ethanol | primates | evolution

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Section: Methodssupporting

confidence: 67%

“…•min •min −1 (76)]. † An alternative sequence representing node 44 with an isoleucine at position 117 (instead of valine, see Fig.…”

Section: −5mentioning

confidence: 99%

Hominids adapted to metabolize ethanol long before human-directed fermentation

Carrigan

Uryasev

Frye

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

126

View full text Add to dashboard Cite

show abstract

“…A plausible explanation is that chronic exposure to ethanol leads to hyperinsulinemia [125], which shifts energy supply from glucose to ketone bodies [65]. In turn, high ketone bodies alongside oxidized carbohydrates and iron overload shift ethanol metabolism from low Km ADH1 (that works in the millimolar range) to high Km alcohol-metabolizing enzymes (that work in the molar range) [65,141] such as cytochrome P450 2E1 (CYP2E1), ADH4, and ADH3 [28,30,66,69,126,142,143]. The net result is that large amounts of ethanol may cause organ damage concurrently with negligible BACs (Figure 2) [28,30,[65][66][67][68].…”

Section: Discussionmentioning

confidence: 99%

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

Medeiros¹,

Lima²

2016

Gastroenterol Hepatol Endosc

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Nonalcoholic fatty pancreas disease (NAFPD) is closely linked to nonalcoholic steatohepatitis (NASH), suggesting that the two conditions share a common etiopathogenetic background. In Addition, growing evidence indicates that endogenous ethanol (EE) plays a fundamental role in NASH pathogenesis. Accordingly, it is intuitively appealing to assume that EE plays also a causative role in NAFPD development. This connection is further supported by the finding that NAFPD shares with alcoholic fatty pancreas disease (AFPD) similar metabolic signaling pathways and histopathological features. However, low blood alcohol concentrations (BAC) along with the alleged inability of gut microbiota to produce toxic amounts of ethanol are the main obstacles to validate the idea of an endogenous alcoholic fatty pancreas disease (EAFPD). Here, we provide a mechanistic explanation reconciling the EAFPD hypothesis with these apparently conflicting observations. The key conclusions of our investigation are as follows. First, ethanol is a prodrug, implicating that under extensive presystemic metabolism BACs can be low and/ or absent. Second, oro-gastrointestinal microbiota may produce higher amounts of ethanol than those required to cause AFPD. Last, livers of NASH/NAFPD individuals overexpress all genes encoding alcohol-metabolizing enzymes identically to livers of patients with alcoholic hepatitis. Even more importantly, the upregulation of these genes is higher in the early steatotic stage of nonalcoholic fatty liver disease than in alcoholic hepatitis. This suggests a greater exposure of the liver, and by extension, of the pancreas, to ethanol in the former than in the latter condition. In summary, this paper provides a mechanistic framework for how NAFPD indeed may be an EAFPD.

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“…Enzym klasy IV jest również wydajny w utlenianiu retinolu ze stałą kinetyczną Km = 0,002 mM [29], ponadto wykazuje częściową ekspresję w ośrodko-wym układzie nerwowym oraz wraz z pozostałymi dehydrogenazami alkoholowymi jest zaangażowany w metabolizm różnych dopaminozależnych neurotransmiterów. Etanol konkuruje z retinolem o miejincreases the duration of activity of the enzyme on ethanol, thus increasing the first-pass metabolism of the substance [1,25].…”

Section: Gastric Dehydrogenaseunclassified

Variation in gastric alcohol dehydrogenase and the risk of alcohol dependence

Całka¹,

Ciesielka²,

Buszewicz³

et al. 2016

amsik

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StreszczenieUzależnienie od alkoholu stanowi problem zarówno medyczny, jak i społeczno-ekonomiczny. Jest zaliczane do chorób o charakterze wieloczynnikowym, czyli takich, za które odpowiadają relacje gen-gen oraz gen-środo-wisko. Wieloośrodkowe badania nad genetycznym podłożem alkoholizmu podkreślają znaczenie genów kodujących enzymy szlaku rozkładu etanolu w organizmie ludzkim, szczególnie dehydrogenazy alkoholowej (ADH) w rozwoju choroby. Z pięciu klas dehydrogenaz alkoholowych związek z uzależnieniem od alkoholu wykazują izoenzymy klasy I i IV. Klasa IV jest szczególnie interesująca ze względu na jej występowanie w górnym odcinku przewodu pokarmowego, głównie w żołądku. Nie wykazano aktywności tego enzymu w wątrobie. Polimorfizm pojedynczych nukleotydów (SNP) genu kodującego tę klasę, czyli ADH7, wpływa na jej aktywność utleniającą etanol w świetle żołądka i tym samym na metabolizm pierwszego przejścia ( FPM) tej substancji. Opublikowane wyniki różnych ośrodków badawczych pokazują, że konkretne zmiany typu SNP w genie ADH7 mają odmienne znaczenie dla ryzyka uzależnienia od alkoholu w zależności od badanej populacji.Słowa kluczowe: ADH7, alkoholizm, metabolizm pierwszego przejścia. AbstractAlcohol dependence is both a medical and socioeconomic problem. The disease is multifactorial, i.e. its development is attributable to gene-gene and gene-environment interactions. Multi-centre studies investigating the genetic background of alcoholism stress the role of genes encoding enzymes of the ethanol decomposition pathway in the human body, particularly alcohol dehydrogenase (ADH), in the development of alcohol dependence. Among five classes of alcohol dehydrogenases, class I and IV isoenzymes have been found to be associated with alcohol dependence. Class IV is of particular interest due to its occurrence in the upper gastrointestinal tract, mainly in the stomach. No activity of the enzyme has been demonstrated in the liver. Single nucleotide polymorphism (SNP) of the gene encoding ADH class IV (ADH7) affects its ethanol-oxidizing activity in the gastric lumen, thereby influencing the first-pass metabolism (FPM) of the substance. The findings published by various research centres have demonstrated that specific SNP changes in the ADH7 gene are of different significance for the risk of alcohol dependence according to the population studied.

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Human class IV alcohol dehydrogenase: kinetic mechanism, functional roles and medical relevance

Cited by 49 publications

References 48 publications

Hominids adapted to metabolize ethanol long before human-directed fermentation

Hominids adapted to metabolize ethanol long before human-directed fermentation

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

Variation in gastric alcohol dehydrogenase and the risk of alcohol dependence

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