Oxidation-reduction cofactors

Vitamins E and K and the Lipid Quinones Are Oxidation-Reduction Cofactors... 

Steenkamp, D. J., and Singer, T. P, 1976, On the presence of a novel covalently bound oxidation-reduction cofactor, iron and labile sulfur in trimethylamine dehydrogenase, Biochem. Biophys. Res. Commun. 71 1289nl295. 

IV. ENAMINES IN OXIDATION-REDUCTION COFACTORS A. Flavin Cofactors... 

Another potential puzzle lies in the difference between the modes of operation of a coenzyme like NAD+ and a prosthetic group like FAD, both of them oxidation-reduction cofactors. The fundamental difference is that a prosthetic group forms a permanent part of the equipment of the enzyme, whereas a coenzyme like NAD+ arrives and departs just like any other substrate. In an oxidation carried out with the help of FAD, the reduced FAD would just have to wait for another substrate molecule to arrive to put it out of its misery and reoxidise it. In a similar reaction with NAD+, the NADH, once produced, would simply leave and And its own way to be reoxidised with the help of another protein parmer. 

In certain bacteria there is a specific nutritional requirement for D-amino acids which are found as components of cell structures or antimetabolites. Bacteria normally meet this need by the conversion of L-amino acids to D-amino acids and in the case of alanine, methionine and tryptophan the evidence suggests that these reactions are directly catalysed by amino acid racemases which have a cofactor requirement for pyridoxal phosphate . An oxidation-reduction cofactor may also be a general feature of racemases of this class. However, the mode of epimerisation of L-phenylalanine to D-phenylalanine necessary for the synthesis of some peptide antibiotics, proceeds in an entirely different way, which as yet has only been partially resolved. 

Many dehydrogenase enzymes catalyze oxidation/reduction reactions with the aid of nicotinamide cofactors. The electrochemical oxidation of nicotinamide adeniiw dinucleotide, NADH, has been studied in depthThe direct oxidation of NADH has been used to determine concentration of ethanol i s-isv, i62) lactate 157,160,162,163) pyTuvate 1 ), glucose-6-phosphate lactate dehydrogenase 159,161) alanine The direct oxidation often entails such complications as electrode surface pretreatment, interferences due to electrode operation at very positive potentials, and electrode fouling due to adsorption. Subsequent reaction of the NADH with peroxidase allows quantitation via the well established Clark electrode. 

Indicine IV-oxide (169) (Scheme 36) is a clinically important pyrrolizidine alkaloid being used in the treatment of neoplasms. The compound is an attractive drug candidate because it does not have the acute toxicity observed in other pyrrolizidine alkaloids. Indicine IV-oxide apparently demonstrates increased biological activity and toxicity after reduction to the tertiary amine. Duffel and Gillespie (90) demonstrated that horseradish peroxidase catalyzes the reduction of indicine IV-oxide to indicine in an anaerobic reaction requiring a reduced pyridine nucleotide (either NADH or NADPH) and a flavin coenzyme (FMN or FAD). Rat liver microsomes and the 100,000 x g supernatant fraction also catalyze the reduction of the IV-oxide, and cofactor requirements and inhibition characteristics with these enzyme systems are similar to those exhibited by horseradish peroxidase. Sodium azide inhibited the TV-oxide reduction reaction, while aminotriazole did not. With rat liver microsomes, IV-octylamine decreased... 

Since many of the transformations undergone by metabolites involve changes in oxidation state, it is understandable that cofactors have been developed to act as electron acceptors/ donors. One of the most important is that based on NAD/NADP. NAD+ can accept what is essentially two electrons and a proton (a hydride ion) from a substrate such as ethanol in a reaction catalysed by alcohol dehydrogenase, to give the oxidized product, acetaldehyde and the reduced cofactor NADH plus a proton (Figure 5.2). Whereas redox reactions on metal centres usually involve only electron transfers, many oxidation/reduction reactions in intermediary metabolism, as in the case above, involve not only electron transfer but... 

In some cases, enzymes require the assistance of coenzymes (cofactors) to ensure the reactions proceed. Coenzymes include vitamins, metal ions, acids, and bases. They can act as transporters or electron acceptors or be involved in oxidation-reduction reactions. At the completion of the reaction, coenzymes are released, and they do not form part of the products. For some reactions that are energetically unfavorable, an energy source provided by the compound adenosine triphosphate (ATP) is needed to ensure the reactions proceed, as shown in the following reactions ... 

Distinct coenzymes are required in biological systems because both catabolic and anabolic pathways may exist within a single compartment of a cell. The nicotinamide coenzymes catalyze direct hydride transfer (from NAD(P)H or to NAD(P)+) to or from a substrate or other cofactors active in oxidation-reduction pathways, thus acting as two-electron carriers. Chemical models have provided... 

The oxidation/reduction of redox cofactors in biological systems is often coupled to proton binding/release either at the cofactor itself or at local amino acid residues, which provides the basic mechanochem-ical part of a proton pump such as that foimd in cytochrome c oxidase (95). Despite a thermodynamic cycle that provides that coupling of protonation of amino acids to the reduction process will result in a 60 mV/pH decrease unit in the reduction potential per proton boimd between the pAa values in the Fe(III) and Fe(II) states, the essential pumping of protons in the respiratory complexes has yet to be localized within their three-dimensional structures. 

This enzyme [EC 1.1.99.8], also referred to as alcohol dehydrogenase (acceptor) and methanol dehydrogenase, catalyzes the oxidation-reduction reaction of a primary alcohol with an acceptor to generate an aldehyde and the reduced acceptor. The cofactor for this enzyme is pyrroloquinoline qutnone (PQQ). A wide variety of primary alcohols can act as the substrate. See also Alcohol Dehydrogenase... 

This enzyme [EC 1.4.99.1] catalyzes the oxidation-reduction reaction of a D-amino acid with an acceptor and water to generate an a-keto acid, ammonia, and the reduced acceptor. The enzyme utilizes FAD as a cofactor. Most D-amino acids, with the noted exceptions of D-aspartate and D-glutamate, can be used as substrates. K. Tsukada (1971) Meth. Enzymol. 17B, 623. 

The first examples of mechanism must be divided into two principal classes the chemistry of enzymes that require coenzymes, and that of enzymes without cofactors. The first class includes the enzymes of amino-acid metabolism that use pyridoxal phosphate, the oxidation-reduction enzymes that require nicotinamide adenine dinucleotides for activity, and enzymes that require thiamin or biotin. The second class includes the serine esterases and peptidases, some enzymes of sugar metabolism, enzymes that function by way of enamines as intermediates, and ribonuclease. An understanding of the mechanisms for all of these was well underway, although not completed, before 1963. 

On the other hand, Feigelson and his associates169,170,172-175 have reported that not only heme but also copper is an essential cofactor in both Pseudomonad and hepatic enzymes and that there are three different oxidation-reduction states of the enzyme, namely, a fully reduced form, E(Cu+, Fe2+) a half-reduced form, E(Cu+, Fe3+) or its valence isomer E(Cu2+, Fe2+) and a fully-oxidized form,... 

RGURE 7 An oxidation-reduction reaction. Shown here is the oxidation of lactate to pyruvate. In this dehydrogenation, two electrons and two hydrogen ions (the equivalent of two hydrogen atoms) are removed from C-2 of lactate, an alcohol, to form pyruvate, a ketone. In cells the reaction is catalyzed by lactate dehydrogenase and the electrons are transferred to a cofactor called nicotinamide adenine dinucleotide. This reaction is fully reversible pyruvate can be reduced by electrons from the cofactor. In Chapter 13 we discuss the factors that determine the direction of a reaction. 

The fifth cofactor of the PDH complex, lipoate (Fig. 16-4), has two thiol groups that can undergo reversible oxidation to a disulfide bond (—S—S—), similar to that between two Cys residues in a protein. Because of its capacity to undergo oxidation-reduction reactions, lipoate can serve both as an electron hydrogen carrier and as an acyl carrier, as we shall see. 

Considering the malo-lactic fermentation microbiologically, several factors are apparent. For example, the enzyme cofactor nicotinamide-adenine dinucleotide (NAD) is required for completion of the reaction, although there is no net oxidation-reduction change in proceeding from L-malic acid to L-lactic acid. Classically, the involvement of NAD in an... 

Biochemically, FMN and FAD act as cofactors, i.e., as covalently bound prosthetic groups, or as noncovalently bound coenzymes in a variety of biological oxidation-reduction reactions, such as ... 

Biochemically, the niacin coenzymes function as cofactors for a number of dehydrogenases due to their oxidation-reduction capabilities (19,93,96). They are involved in the metabolism of carbohydrates, fatty acids, and amino acids. Nicotinamide can also participate in nonredox reactions, such as the ribosylation of ADP. 

Typical reactions catalyzed by UGT enzymes require the cofactor uridine diphosphate-glucuronic acid, UDPGA. However, the C-terminus of all UGT enzymes contains a membrane-spanning domain that anchors the enzyme in the endoplasmic reticulum, and the enzyme faces the lumen of the endoplasmic reticulum, where it is ideally placed to conjugate lipophilic xenobiotics and their metabolites generated by oxidation, reduction, or hydrolysis. The lumenal... 

Other biomimetic reactions are based on the catalytic properties of metal ions. Many enzymes require metal ions that function, in one way or another, in oxidation-reduction processes. The wide range of such metal-ion reactions precludes mentioning more than a few in addition to the iron-porphyrin class, and in addition to chlorophyll, a number of enzymes require cobalamin as cofactor ferridoxin and high-potential iron proteins require iron-sulfur clusters, and nitrog-... 

Substances arising from foodstuffs—glucose, fatty acids, amino acids, and others—yield energy by being oxidized that is, they lose electrons. Such electrons are lost to the reduction-oxidation (redox) cofactors NAD+ and FAD and, less commonly, to others. Because oxidation must take place at body tempera-... 

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