Flavin adenine dinucleotide mechanism

Disulfoton causes neurological effects in humans and animals. The mechanism of action on the nervous system depends on the metabolism of disulfoton to active metabolites. The liver is the major site of metabolic oxidation of disulfoton to disulfoton sulfoxide, disulfoton sulfone, demeton S-sulfoxide and demeton S-sulfone, which inhibit acetylcholinesterase in nervous tissue. These four active metabolites are more potent inhibitors of acetylcholinesterase than disulfoton. Cytochrome P-450 monooxygenase and flavin adenine dinucleotide monooxygenase are involved in this metabolic activation. The active metabolites ultimately undergo nonenzymatic and/or enzymatic hydrolysis to more polar metabolites that are not toxic and are excreted in the urine. 

The relaxation approach has played an important role in our understanding of the mechanisms of complex formation in solution (Chap. 4) 39,i4o -pjjg qj computer programs has now eased the study of multiple equilibria. For example, four separate relaxation effects with t s ranging from 100 xs to 35 ms are observed in a temperature-jump study of the reactions of Ni with flavin adenine dinucleotide (fad) (Eqn. (8.121)). The complex relaxation... 

There are demethylases which act like amine oxidases that are dependent in their mechanism on their cosubstrate flavine adenine dinucleotide (FAD). So far, lysine-specific demethylase 1 (LSDl) is the only representative of this class [62]. LSDl, as an amine oxidase leads to oxidation of the methylated lysine residue, generating an imine intermediate, while the protein-bound cosubstrate FAD is reduced to FAD H2. In a second step, the imine intermediate is hydrolyzed to produce the demethylated histone lysine residue and formaldehyde. Importantly the reduced cosubstrate is regenerated to its oxidized form by molecular oxygen, producing hydrogen peroxide (Figure 5.7) [62, 63]. 

The hydroxynitrile lyase (HNL) class of enzymes, also referred to as oxynitrilases, consists of enzymes that catalyze the formation of chiral cyanohydrins by the stereospecific addition of hydrogen cyanide (HCN) to aldehydes and ketones (Scheme 19.36).275 279 These chiral cyanohydrins are versatile synthons, which can be further modified to prepare chiral a-hydroxy acids, a-hydroxy aldehydes and ketones, acyloins, vicinal diols, ethanolamines, and a- and P-amino acids, to name a few.280 Both (R)- and (.S )-selective HNLs have been isolated, usually from plant sources, where their natural substrates play a role in defense mechanisms of the plant through the release of HCN. In addition to there being HNLs with different stereo-preferences, two different classifications have been defined, based on whether the HNL contains a flavin adenine dinucleotide (FAD) co-factor. 

Reduction of the heme iron of cytochromes P450 to the ferrous state 3 is necessary for the binding and subsequent activation of atmospheric dioxygen. Initially, two electrons are derived from NAD(P)H by flavin adenine dinucleotide (FAD)-containing proteins and then are used sequentially via one-electron transfers. AU cytochromes P450 can be divided into two main classes with respect to the reduction mechanism and the structure of their immediate redox partner. The first class includes most soluble... 

Figure 8.23. Mechanism-Based (Suicide) Inhibition. Monoamine oxidase, an enzyme important for neurotransmitter synthesis, requires the cofactor FAD (flavin adenine dinucleotide). AA -Dimethylpropargylamine inhibits monoamine oxidase by covalently modifying the flavin prosthetic group only after the inhibitor is first oxidized. The N-5 flavin adduct is stabilized by the addition of a proton.

Bacterial mercuric reductase is a unique metal-detoxification biocatalyst, reducing mercury(II) salts to the metal. The enzyme contains flavin adenine dinucleotide, a reducible active site disulfide (Cys 135, Cys i4o), and a C-terminal pair of cysteines (Cys 553, Cys 559). Mutagenesis studies have shown that all four cysteines are required for efficient mercury(II) reduction. Mercury Lm-EXAFS studies for mercury(II) bound to both the wild-type enzyme and a very low-activity C-terminal double-alanine mutant (Cys 135, Cys uo, Ala 553, Ala 559) suggest the formation of an Hg(Cys)2 complex in each case (39). The Hg—S distances obtained were 2.31 A and are consistent with the correlation of bond length with coordination number presented above. Thus, no evidence was obtained for coordination of mercury(II) by all four active-site cysteines in the wild-type mercuric reductase. However, these studies do not define the full extent of the catalytic mechanism for mercury(II) reduction, and it is possible that a three- or four-coordinate Hg(Cys) complex is a key intermediate in the process. 

Pinto J, Huang YP, Rivlin RS. Mechanisms underlying the differential effects of ethanol on the bioavailability of riboflavin and flavin adenine dinucleotide. J Clin Invest 1987 79 1343-8. 

The ACDs constitute a family of flavin-containing enzymes with at least nine members that catalyze the a,/3-oxidation of fatty acyl-CoA thioesters (see Chapter 7.03). Interest in the structure and mechanism of ACDs stems in part from their potential role in diseases such as sudden infant death syndrome. Most ACDs are homotetramers binding one molecule of flavin adenine dinucleotide (FAD) per subunit, and MCAD, from the mitochondrial /3-oxidation pathway, is the most heavily studied family member. Several reviews on the structure and mechanism of the ACDs have appeared, and the reader s attention is drawn to Thorpe and Kim, Kim and Miura, and Ghisla and Thorpe. ... 

This paper describes some of the results of our investigations of the two FAD (flavin adenine dinucleotide)-containing monooxygenases. We also discuss the mechanism of activation of molecular oxygen by these enzymes. 

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