Alcohols, enzymic oxidation

Step 3 of Figure 29.12 Oxidation and Decarboxylation (2K,3S)-lsocitrate, a secondary alcohol, is oxidized by NAD+ in step 3 to give the ketone oxalosuccinate, which loses C02 to givea-ketoglutarate. Catalyzed by isocitrate dehydrogenase, the decarboxylation is a typical reaction of a /3-keto acid, just like that in the acetoacetic ester synthesis (Section 22.7). The enzyme requires a divalent cation as cofactor, presumably to polarize the ketone carbonyl group. 

Aldehydes are oxidized to carboxylic acids. A major enzyme responsible for this oxidation is aldehyde dehydrogenase (see Aldehyde Dehydrogenases section in this chapter) (79) however, other enzymes such as AO and cytochromes P450 can also mediate the oxidation of aldehydes as discussed (discussed earlier in this chapter). Ketones are not substrates for aldehyde dehydrogenase for the same reason that tertiary alcohols cannot be oxidized by ALD. Unlike the oxidation of alcohols, the oxidation of aldehydes is irreversible. Aldehydes are usually toxic and therefore there are aldehyde dehydrogenases in virtually all cells and in most compartments within cells. 

Since the oxidative polymerization of phenols is the industrial process used to produce poly(phenyleneoxide)s (Scheme 4), the application of polymer catalysts may well be of interest. Furthermore, enzymic, oxidative polymerization of phenols is an important pathway in biosynthesis. For example, black pigment of animal kingdom "melanin" is the polymeric product of 2,6-dihydroxyindole which is the oxidative product of tyrosine, catalyzed by copper enzyme "tyrosinase". In plants "lignin" is the natural polymer of phenols, such as coniferyl alcohol 2 and sinapyl alcohol 3. Tyrosinase contains four Cu ions in cataly-tically active site which are considered to act cooperatively. These Cu ions are presumed to be surrounded by the non-polar apoprotein, and their reactivities in substitution and redox reactions are controlled by the environmental protein. 

Alcohols are oxidized to aldehydes by the liver enzyme alcohol dehydrogenase, and aldehydes to carboxylic acids by aldehyde dehydrogenase. In mammals, monooxygenases can be induced by plant secondary metabolites such as a-pinene, caffeine, or isobornyl acetate. Reduction is less common and plays a role with ketones that cannot be further oxidized. Hydrolysis, the degradation of a compound with addition of water, is also less common than oxidation. 

UDP-GA is formed from UDPglucose (see Box 12.4) by enzymic oxidation of the primary alcohol group. We have already noted in Section 12.6 that UDPglucose is also the biochemical precursor of glucose-containing polysaccharides, e.g. starch and glycogen (see Section 12.7). 

In animals, ascorbic acid is synthesized in the liver from o-glucose, by a pathway that initially involves specific enzymic oxidation of the primary alcohol function, giving o-glucuronic acid (see Section 12.8). This is followed by reduction to L-gulonic acid, which is effectively reduction of the carbonyl function in the ring-opened hemiacetal. 

VAO activity was measured with a mixture of 1 mM veratryl alcohol, 250 mM sodium tartrate buffer, pH 5.0 and enzyme. Oxidation to vera-... 

The full paper on the synthesis of onikulactone and mitsugashiwalactone (Vol. 7, p. 24) has been published.Whitesell reports two further useful sequences (cf. Vol. 7, p. 26) from accessible bicyclo[3,3,0]octanes which may lead to iridoids (123 X=H2, Y = H) may be converted into (124) via (123 X = H2, Y = C02Me), the product of ester enolate Claisen rearrangement of the derived allylic alcohol and oxidative decarboxylation/ whereas (123 X = 0, Y = H) readily leads to (125), a known derivative of antirride (126) via an alkylation-dehydration-epoxi-dation-rearrangement sequence. Aucubigenin (121 X = OH, R = H), which is stable at —20°C and readily obtained by enzymic hydrolysis of aucubin (121 X = OH, R = j8-Glu), is converted by mild acid into (127) ° with no dialdehyde detected sodium borohydride reduction of aucubigenin yields the non-naturally occurring isoeucommiol (128 X=H,OH) probably via the aldehyde (128 X = O). ... 

The remaining three steps are accomplished without purification of the intermediate products. The secondary hydroxy group is protected by acetylation and the benzyl ether is removed by hydrogenolysis to provide a primary alcohol. The alcohol is oxidized to a carboxylic acid by ruthenium(III) chloride or pyridinium dichromate. This method has been applied to the synthesis of various enzyme inhibitors containing the 1-hydroxyethylene isostere. 

Several of the B vitamins function as coenzymes or as precursors of coenzymes some of these have been mentioned previously. Nicotinamide adenine dinucleotide (NAD) which, in conjunction with the enzyme alcohol dehydrogenase, oxidizes ethanol to ethanal (Section 15-6C), also is the oxidant in the citric acid cycle (Section 20-10B). The precursor to NAD is the B vitamin, niacin or nicotinic acid (Section 23-2). Riboflavin (vitamin B2) is a precursor of flavin adenine nucleotide FAD, a coenzyme in redox processes rather like NAD (Section 15-6C). Another example of a coenzyme is pyri-doxal (vitamin B6), mentioned in connection with the deamination and decarboxylation of amino acids (Section 25-5C). Yet another is coenzyme A (CoASH), which is essential for metabolism and biosynthesis (Sections 18-8F, 20-10B, and 30-5A). 

Recall from Section 1.9 that some molecules can exist as chiral enantiomers that are mirror images of each other. Although enantiomers may appear to be superficially identical, they may differ markedly in their metabolism and toxic effects. Much of what is known about this aspect of xenobiotics has been learned from studies of the metabolism and effects of pharmaceuticals. For example, one of the two enantiomers that comprise antiepileptic Mesantoin is much more rapidly hydroxylated in the body and eliminated than is the other enantiomer. The human cytochrome P-450 enzyme denoted CYP2D6 is strongly inhibited by quinidine, but is little affected by quinine, an optical isomer of quinidine. Cases are known in which a chiral secondary alcohol is oxidized to an achiral ketone, and then reduced back to the secondary alcohol in the opposite configuration of the initial alcohol. 

A common step in the metabolism of alcohols is carried out by alcohol dehydrogenase enzymes that produce aldehydes from primary alcohols that have the -OH group on an end carbon and produce ketones from secondary alcohols that have the -OH group on a middle carbon, as shown by the examples in Reactions 7.3.6 and 7.3.7. As indicated by the double arrows in these reactions, the reactions are reversible and the aldehydes and ketones can be converted back to alcohols. The oxidation of aldehydes to carboxylic acids occurs readily (Reaction 7.3.8). This is an important detoxication process because aldehydes are lipid soluble and relatively toxic, whereas carboxylic acids are more water soluble and undergo phase n reactions leading to their elimination. 

A single enzyme is sometimes capable of many various oxidations. In the presence of NADH (reduced nicotinamide adenine dinucleotide), cyclohexanone oxygenase from Acinetobacter NCIB9871 converts aldehydes into acids, formates of alcohols, and alcohols ketones into esters (Baeyer-Villiger reaction), phenylboronic acids into phenols sulfides into optically active sulfoxides and selenides into selenoxides [1034], Horse liver alcohol dehydrogenase oxidizes primary alcohols to acids (esters) [1035] and secondary alcohols to ketones [1036]. Horseradish peroxidase accomplishes the dehydrogenative coupling [1037] and oxidation of phenols to quinones [1038]. Mushroom polyphenol oxidase hydroxylates phenols and oxidizes them to quinones [1039]. 

Conventional laboratory oxidation of the monodeuteriated ethanol 24 gives ethanal (acetaldehyde), which contains 50% of the deuterium present in 24 (Scheme 8.1). However, enzymes are chiral, and enzymic oxidation (by yeast alcohol dehydrogenase and NAD+) removes exclusively in the oxidation of ethanol to ethanal HR is labelled as D in Scheme 8.2. Clearly, the molecule of ethanol is presented to the chiral enzyme so as to form a unique diastereoisomeric complex in which only the proton can be removed in the oxidative elimination. 

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