Sequential oxidations, dehydrogenases that

Since, in the microsomal membrane, two NADP+-dependent dehydrogenases are present that catalyze the sequential oxidation of glucose-6-phosphate (G6P) to ribulose-5-phosphate ... 

The growth of Acetobacter species on ethanol results in the accumulation of acetate, which is then completely oxidized by the phenomenon termed acetate overoxidation. The sequential oxidation of ethanol and acetate leads to a diauxic growth profile that is characterized by acetate accumulation in the first exponential growth phase and complete oxidation of the accumulated acetate in the secrnid exponential phase (Saeki et al. 1997). However, in some conditions, ethanol is oxidized to acetate both in the periplasm, by membrane-bound PQQ-dependent ADH and aldehyde dehydrogenase (ALDH), and in the cytoplasm, by soluble NAD (P) -dependent ADH and ALDH. These conditimis are unfavorable for vinegar production because acetate generated in the cytoplasm tends to be rapidly metabolized via the tricarboxylic acid (TCA) cycle. 

Dimethylhydrazine is metabolized by a sequence of oxidation steps, first dehydrogenation to azomethane, A -oxidation of this to azoxymethane and finally a C-oxidation to methylazoxymethanol (Fiala, 1975, 1977). This last metabolite decomposes to give the highly reactive methyldiazonium ion to which the carcinogenicity of the compound has been attributed. The sequential nature of these oxidation steps has been shown in the isolated perfused rat liver (Wolter Frank, 1982). Fiala (1977) showed that the C-oxidation of azoxymethane to methylazoxymethanol is catalysed by hepatic microsomes, while Schoental (1973) found that methylazoxymethanol was converted to the corresponding aldehyde by an NAD-dependent dehydrogenase. 

The bacterial enzyme chorismate mutase-prephenate dehydrogenase is peculiar because it is a single protein unit with two catalytic activities. It catalyzes the sequential reactions of mutation of chorismate to prephenate and then the reaction that leads to the formation of phenylalanine and tyrosine, through oxidation of prephenate. The first of these reactions is interesting because it is one of the few strictly single-substrate enzymatic reactions it entails... 

Many enzymes that have NAD+ or NADH as a substrate exhibit the sequential ordered mechanism. Consider lactate dehydrogenase, an important enzyme in glucose metabolism (Section 16.1.9). This enzyme reduces pyruvate to lactate while oxidizing NADH to NAD+. 

Pyruvate must first be transported into mitochondria by a specific carrier that cotransports a proton to maintain electrical neutrality. Inside mitochondria pyruvate undergoes oxidative decarboxylation by three enzymes that function sequentially and are present as a complex known as the pyruvate dehydrogenase complex. The overall reaction is physiologically irreversible, has a high negative AG° (—8.0 kcal/mol, or —33.5 kJ/mol), and commits pyruvate to the formation of acetyl-CoA ... 

Fatty alcohohNAD oxidoreductase is a complex enzyme which consists of two separate proteins that sequentially catalyze the oxidation of fatty alcohol to fatty aldehyde and to fatty acid that is to say a fatty alcohol dehydrogenase and a fatty aldehyde dehydrogenase (FALDH) activity. Sjogren-Larsson cells were selectively deficient in the FALDH component and had normal activity of fatty alcohol dehydrogenase. Intact fibroblast oxidized octadecanol to fatty acid at <10% of the normal rate but oxidized octadecanal normally confirming that FALDH is specifically affected (Rizzo and Craft, 1991). 

In the electron transport chain, electrons donated by NADH or FAD(2H) are passed sequentially through a series of electron carriers embedded in the inner mitochondrial membrane. Each of the components of the electron transfer chain is oxidized as it accepts an electron, and then reduced as it passes the electrons to the next member of the chain. From NADH, electrons are transferred sequentially through NADH dehydrogenase (complex 1), CoQ (coenzyme Q), the cytochrome b-Ci complex (complex 111), cytochrome c, and finally cytochrome c oxidase (complex IV). NADH dehydrogenase, the cytochrome b-Ci complex and cytochrome c oxidase are each multisubunit protein complexes that span the inner mitochondrial membrane. CoQ is a lipid soluble quinone that is not protein-bound and is free to diffuse in the lipid membrane. It transports electrons from complex 1 to complex 111 and is an intrinsic part of the proton pumps for each of these complexes. Cytochome c is a small protein in the inner membrane space that transfers electrons from the b-Ci... 

Substrate specificities can be broad and overlapping both among CYP family members and between CYPs and FMOs, and since metabolic transformations are often sequential (e.g. aliphatic hydroxylation being followed by oxidation by alcohol dehydrogenase, further oxidation to the acid, etc.), many enzymes and many metabolites can be involved in processing a single drug. Only a few of the most important enzymes involved in Phase I transformations have been mentioned here. For these and many others (monoamine oxidase, xanthine oxidase, etc.), further information can be found in the previously cited reviews. Bear in mind too that not all Phase I reactions are oxidative enzymes like carbonyl reductases are important in metabolism as well. 

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