Coenzyme termination step

Experiments have been carried out to mimic the reactions of model systems for coenzyme F430 that is involved in the terminal step in the biosynthesis of methane, and that is able to dechlorinate CCI4 successively to CHCI3 and CH2CI2 (Krone et al. 1989). Nickel(I) isobacteriochlorin anion was generated electrolytically and used to examine the reactions with alkyl halides in dimethylformamide (Helvenston and Castro 1992). The three classes of reaction were the same as those observed with Fe(II) deuteroporphyrin IX that have already been noted. 

Little effort has been devoted to ascertain how the coenzyme is re-formed (the termination step). In the radical initiation step (ii, Figure 3), deoxyadenosine is formed. To re-form the Co-C bond to the 5 position of the nucleoside, a methyl group in the 5 -deoxy adenosine must be activated. Such activation requires either H atom abstraction, perhaps by the amino acid side chain radical or by a rearranged radical intermediate derived from the substrate (iv, Figure 3). This step is still not well understood. In the first edition of this volume [75], I expressed the hope that the steps that regenerate the coenzyme would become obvious once the rearrangement process was understood. Recent studies [67] to be described... 

The terminal step in methane generation by several methanogenic organisms, of which the best studied is the archaeon Methanobacterium thermoautotrophicum, is catalyzed by the enzyme S-methyl coenzyme M reductase (methylreductase, EC 1.8.-.-). This enzyme contains a macrocyclic tetrapyrrole-derived cofactor, F430, at the active site coordinating Ni(II) in the resting state. A Ni(I) state (Ni1F430) has been proposed as the active form of the cofactor. Extensive mechanistic and spectroscopic studies have been performed on the holoenzyme, isolated cofactor, and various synthetic model compounds. These studies are summarized in... 

All the individual steps are catalyzed by enzymes NAD" (Section 15 11) is required as an oxidizing agent and coenzyme A (Figure 26 16) is the acetyl group acceptor Coen zyme A is a thiol its chain terminates m a sulfhydryl (—SH) group Acetylation of the sulfhydryl group of coenzyme A gives acetyl coenzyme A... 

The neurotransmitter must be present in presynaptic nerve terminals and the precursors and enzymes necessary for its synthesis must be present in the neuron. For example, ACh is stored in vesicles specifically in cholinergic nerve terminals. It is synthesized from choline and acetyl-coenzyme A (acetyl-CoA) by the enzyme, choline acetyltransferase. Choline is taken up by a high affinity transporter specific to cholinergic nerve terminals. Choline uptake appears to be the rate-limiting step in ACh synthesis, and is regulated to keep pace with demands for the neurotransmitter. Dopamine [51 -61-6] (2) is synthesized from tyrosine by tyrosine hydroxylase, which converts tyrosine to L-dopa (3,4-dihydroxy-L-phenylalanine) (3), and dopa decarboxylase, which converts L-dopa to dopamine. 

Earlier in this chapter, it was mentioned that many of the nonprotein amino acids are components of nonribosomal peptides. During such a biosynthesis, the peptide is attached to a carrier protein through a thioester bond, until chain termination occurs and the final product is released. The carrier protein is posttranslationally modified by the attachment of a phosphopantetheinyl group from coenzyme A. This step gives rise to the active carrier protein with a phosphopantetheine arm upon which amino acids are added to during NRPS. As an example, loading of isoleucine onto the carrier protein is depicted below (Scheme 5). Further details about nonribosomal peptide syntheses and enzymatic reactions can be found in Chapter 5.19. 

The fourth and last step of the /3-oxidation cycle is catalyzed by acyl-CoA acetyltransferase, more commonly called thiolase, which promotes reaction of /3-ketoacyl-CoA with a molecule of free coenzyme A to split off the carboxyl-terminal two-carbon fragment of the original fatty acid as acetyl-CoA The other product is the coenzyme A thioester of the fatty acid, now shortened by two carbon atoms (Fig. 17-8a). This reaction is called thiolysis, by analogy with the process of hydrolysis, because the /3-ketoacyl-CoA is cleaved by reaction with the thiol group of coenzyme A... 

Sex pheromones in the Lepidoptera are multi-component mixtures consisting mostly of olefinic compounds possessing a terminal aldehyde, alcohol, or acetate moiety. Besides functional group differences, the constituents of lepidopteran sex pheromones vary in hydrocarbon chain length and in the specific number, location, and geometry of double bonds. These chemical structures are formed in biosynthetic pathways involving a limited number of enzymatic steps believed to use fatty-acyl thioesters of coenzyme A (acyl-CoA) as substrates. Key reactions are desaturation, limited [3-oxidation, and a small number of terminal functional group modifications (reviewed in Chapter 3). 

In the final step of methanogenesis, methyl coenzyme M reductase catalyzes the reaction of methyl coenzyme M (CH3 S-CoM) with coenzyme B (CoB-SH) to form methane and the CoM-S-S oB heterodisulfide. The heterodisulfide functions as the terminal electron acceptor of... 

Fig. 2.13 Biosynthesis of saturated fatty acids in plants and animals. Palmitate is formed by successive additions of malonyl coenzyme A to the enzyme-bound chain, with C02 being lost at each addition.This results in chain elongation by a (CH2)2 unit at each step. Details of the formation of butyryl (C4) from acetyl (C2) are shown, while the subsequent six further additions, terminating in palmitate, proceed similarly.

Choline acetyltransferase catalyzes the synthesis of ACh—the acetylation of choline with acetyl coenzyme A (Co A). Choline acetyltransferase, like other protein constituents of the neuron, is synthesized within the perikaryon and then is transported along the length of the axon to its terminal. Axonal terminals contain a large number of mitochondria, where acetyl CoA is synthesized. Choline is taken up from the extracellular fluid into the axoplasm by active transport. The synthetic step occurs in the cytosol most of the ACh is then sequestered within synaptic vesicles. Inhibitors of choline acetyltransferase have no therapeutic utility, in part because the uptake of choline, not the activity of the acetyltransferease, is rate-limiting in ACh biosynthesis. 

The 3-oxidation cycle activates A VPA to its coenzyme A derivative and, through sequential steps of 3-oxidation, yields 3-oxo 2-propyl-4-pentenoic acid. This final metabolite is believed to be a reactive electrophilic species that alkylates 3-ketoacyl-CoA thiolase (the terminal enzyme of 3-oxidation) by means of a Michael-type addition through nucleophilic attack at the olefinic terminus. ... 

Rat liver extracts use thiamine rather than thiamine monophosphate for the formation of thiamine pyrophosphate. Therefore, the formation of coenzyme appears to be a one-step reaction between thiamine and ATP. This assumption is supported by experiments using ATP labeled in the terminal phosphate. When such a precursor is added to the incubation mixture, thiamine pyrophosphate labeled in the terminal phosphate only is formed. A thiamine pyrophos-... 

Biosynthesis of ACh involves a reversible reaction in which an acetyl group is transferred from acetyl coenzyme A to choline by the enzyme choline acetyltransferase. The rate-limiting step in ACh s)mthesis is the availability of choline, which is transported into neuronal terminals from the extracellular space by sodium-dependent, high-affinity uptake systems. ACh s)mthesized in the cytosol is stored in vesicles via the action of the vesicular ACh transporter. In response to an action potential, vesicular ACh is released by exocytosis from cholinergic nerve terminals, where it can interact with two major types of receptors muscarinic... 

NADH and FADHg are produced as a result of substrate level dehydrogenations. Oxidation of these reduced coenzymes by oxygen is accomplished by the intervention of a series of electron carriers between the primary reductant and the terminal oxidant (Fig. 2). The electron-transport components represent redox couples of increasing redox potential and are therefore favored thermodynamically. The respiratory chain can be separated into four multienzyme complexes NADH-Q reductase (complex I), succinate-Q reductase (complex II), QH2"Cytochrome c reductase (complex III), and cytochrome c oxidase (complex IV). At each of these successive oxidation-reduction steps, a certain amount of free energy is available, the amount being determined by the difference in the oxidation-reduction potential of the two sequential components. The difference in the redox potential between... 

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