Coenzymes nucleotide derivatives

Examples of coenzymes vitamin-derived nucleotides for example adenosine phosphates ATP, ADP, AMP nicotinamide derivatives NAD+, NADH, NADP+, NADPH flavin derivatives FAD, FADH2 coenzyme A (abbreviated to CoA, CoASH or CoA-SH). 

Coenzyme A is another adenine nucleotide derivative, with its primary functional group, a thiol, some distance away from the nucleotide end of the molecule. This thiol plays an important role in biochemistry via its ability to form thioesters with suitable acyl compounds (see Box 7.18). We have seen how thioesters are considerably more reactive than oxygen esters, with particular attention being paid to their improved ability to form enolate anions, coupled with thiolates being excellent leaving groups (see Box 10.8). 

CoA, the coenzyme A derivative of acetoacetate, reduces its reactivity as a substrate for /3-ketoacyl-CoA transferase (an enzyme of lipid metabolism) by a factor of 106. Although this requirement for adenosine has not been investigated in detail, it must involve the binding energy between enzyme and substrate (or cofactor) that is used both in catalysis and in stabilizing the initial enzyme-substrate complex (Chapter 6). In the case of /3-ketoacyl-CoA transferase, the nucleotide moiety of coenzyme A appears to be a binding handle that helps to pull the substrate (acetoacetyl-CoA) into the active site. Similar roles may be found for the nucleoside portion of other nucleotide cofactors. 

In addition to their role as the building blocks of proteins, amino acids are precursors of many specialized biomolecules, including hormones, coenzymes, nucleotides, alkaloids, cell wall polymers, porphyrins, antibiotics, pigments, and neurotransmitters. We describe here the pathways to a number of these amino acid derivatives. 

Protein enzymes frequently operate with the help of metal ions and with that of organic cofactors, which either are covalently bound to the enzyme molecule (prosthetic groups) or act in free, soluble form (coenzymes). As is to be expected, these cofactors serve mostly as carriers in transfer reactions. Several are nucleotide derivatives or have a nucleotide-like structure, thus being related to nucleic acid components. Many contain a vitamin in their molecule. 

The D-enantiomeric amino acids form by nonprotein synthesis inside bacteria in the form of peptide antibiotics. Although proteins predominate in today s DNA world, one assumes that proteins were in a minority at the beginning of the RNA world. It is likely that several pathways independently produced the first smaller peptides early on. Many essential coenzymes consist not only of nucleotide derivatives but also amino acids Coenzyme A, NADH+, S-adenosyl-methionine, tetrahydrofolate, and many more, see below. 

Purines and pyrimidines are functionally operative as nucleotide derivatives. These are present as intracellular pool ingredients and are used as major components of nucleic acids, as well as many coenzymes. Regulation of a variety of metabolic processes is required to ensure optimal amounts and a balanced distribution of the many different forms purine and pyrimidine classes, ribose and deoxyribose derivatives, and mono-, di-, and triphosphates. 

Most biochemically active coenzymes are either nucleotides or compounds which could be derived from nucleotides. 

Fluorimetric methods are useful for monitoring reactions involving the nucleotide coenzymes. The natural fluorescence of the reduced forms in the region of 460 nm can be used in kinetic assays. However, this fluorescence is destroyed at pH values below 2.0, whereas any oxidized forms of the coenzymes present are stable. If the pH of the solution is then raised above 10.5 and heated, the oxidized forms are themselves converted to fluorescent derivatives. This latter procedure lends itself to fixed time assays such as is illustrated in Procedure 8.6. 

Phosphoric acid molecules can form acid-anhydride bonds with each other. It is therefore possible for two nucleotides to be linked via the phosphate residues. This gives rise to dinucleotides with a phosphoric acid-anhydride structure. This group includes the coenzymes NAD(P) " and CoA, as well as the flavin derivative FAD (1 see p. 104). 

Folate, the anion of folic acid, is made up of three different components—a pteridine derivative, 4-aminobenzoate, and one or more glutamate residues. After reduction to tetrahydrofolate (THF), folate serves as a coenzyme in the Q metabolism (see p. 418). Folate deficiency is relatively common, and leads to disturbances in nucleotide biosynthesis and thus cell proliferation. As the precursors for blood cells divide particularly rapidly, disturbances of the blood picture can occur, with increased amounts of abnormal precursors for megalocytes megaloblastic anemia). Later, general damage ensues as phospholipid... 

Two vitamins, nicotinamide and pyridoxine (vitamin B6), are pyridine derivatives. Nicotinamide participates in two coenzymes, coenzyme I (65 R = H) which is known variously as nicotinamide adenine dinucleotide (NAD) or diphosphopyridine nucleotide (DPN), and coenzyme II (65 R = P03H2) also called triphosphopyridine nucleotide (TPN) or nicotinamide adenine dinucleotide phosphate (NADP). These are involved in many oxidation-reduction processes, the quaternized pyridine system acting as a hydrogen acceptor and hydrogen donor. Deficiency of nicotinamide causes pellagra, a disease associated with an inadequately supplemented maize diet. Nicotinic acid (niacin) and its amide are... 

This toxin subunit is an enzyme, an ADP-ribo-syltransferase which catalyzes transfer of ADP-ribosyl units from the coenzyme NAD+ to specific arginine side chains to form N-ADP-ribosyl derivatives of various proteins. Of the proteins modified by cholera toxin, the most significant is the guanyl nucleotide regulatory protein Gs of the adenylate cyclase system.C/f/h ADP ribosylation of arginine 201 of the a subunit of protein Gs inhibits the GTP hydrolysis that normally allows the protein to relax to an unactivated form.e The ADP-ribosylated Gs keeps adenylate cyclase activated continuously and... 

The reduced form of the respiratory coenzyme diphosphopyridine nucleotide (DPNH), which is vitally important for all cellular metabolism, is changed by dilute acid to a substance that, in the light of the following model experiments, may be a covalent hydrate. The 1,4-and 1,6-dihydro derivatives of l-benzylpyridine-3-carboxamide furnish a single substance when dissolved in dilute acid at 20° and the solution is basified. The stable yellow product, which has a prominent peak at 292 nm, was assigned the constitution 1-benzyl-6-hydroxy-1,4,5,6-tetra-hydropyridine-3-carboxamide61 (see Scheme 2). 3-Acetyl-1 -benzyl- 1,4-... 

It is to be noted that nucleoside 5-pyrophosphates containing glucose104 [for example, uridine 5-(D-glucosyl dihydrogen pyrophosphate)] and other hexoses have been isolated as part of a series of coenzymes. Since the hexose is linked to the nucleotide by way of the pyrophosphate group, these coenzymes are more properly to be considered as derivatives of nucleotides and thus fall outside the scope of this Chapter. 

Although the nicotinamide nucleotide coenzymes function in a large number of oxidation and reduction reactions, thus carmot be exploited as a means of assessing the state of the body s niacin reserves, because the coenzymes are not firmly attached to their apoenzymes, as are coenzymes derived from thiamin (Section 6.5.3), riboflavin (Section 7.5.3), and vitamin Be (Section 9.5.3), but act as cosubstrates of the reactions, binding to and leaving the enzyme as... 

The coenzyme B12 molecule consists of several unique stractural units the corrin ligand, the intramolecularly coordinating nucleotide function, the corrin-bound Co -ion, and the organometallically bound 5 -deoxyadenosyl ligand (Figure 3). The cyanide derivative, vitamin B12 (1), is an isolation artifact that appears not to have a physiological role itself ... 

The various photochemical studies of these compounds have been conducted primarily because of the interest of researchers in the synthesis, properties, and biological activity of vitamin and its derivatives. The structure of vitamin Bj2, as determined by Crowfoot-Hodgkin et al. 109), is shown in Fig. 2. It consists of cobalt in a corrin ring complexed axially by an a-S, 6-dimethylbenzimidazole nucleotide and by cyanide ion. Replacement of the axial CN by a methyl group gives methylcobalamin, and by 5 -deoxyadenosine gives coenzyme Bj2. The formal oxidation state of... 

The purine ring system is undoubtedly among the most ubiquitous of all the heterocyclic compounds. This arises not only from the universal occurrence of adenine and guanine in DNA and RNA and of additional modified derivatives in the various tRNAs but also from the subsidiary uses of the ring system in very many biochemical systems Indeed across the whole spectrum of biochemical reactions in living systems there is hardly a reaction sequence which does not involve in some way a purine derivative such as the adenosine or guanosine mono-, di- and tri-phosphates, associated cyclic phosphates and nucleotide coenzymes. 

Nucleotides are important constituents not only of RNA and DNA, but also of a number of other key biomolecules. Coenzymes NAD+ and FAD, prominent in oxidation-reduction reactions, have ADP as an important constituent. The acyl-group activation compound, coenzyme A, is also derived from ATP. 

---