Nucleotide co-enzymes

Lord Todd For his work on nucleotides and nucleotide co-enzymes. 1968 Lars Onsager For the discovery of the reciprocal relations bearing his name, which are fundamental for the thermodynamics of... 

Lord (Alexander R.) Todd (United Kingdom) for his work on nucleotides and nucleotide co-enzymes. Todd laid the foundation for future research in biochemistry, genetics, and biology surrounding the structures and roles of nucleotides in living organisms. He established the chemical structures of nucleotides, and established the (extremely important) role of phosphorylation in biochemical processes. 

NAD = nicotinamide adenine dinucleotide (diphosphopyridine nucleotide, co-enzyme I)... 

Redox catalysis Zn, Fe, Cu, Mn, Mo, Co, V Se, Cd, Nl Enzymes (see Table 11.4 for more Information) Reactions with oxygen (Fe, Cu) Oxygen evolution (Mn) Nitrogen fixation (Fe, Mo) Inhibition of llpid peroxidation (Se) Carbonic anhydrase (Cd) Reduction of nucleotides (Co) Reactions with H2 (Nl) Bromoperoxidase activity (V)... 

Alexander Todd Great Britain nucleotides and their co-enzymes... 

IPC serves as a powerful tool in many fields of life science. Nucleotides, nucleosides, and related compounds play important roles as structural units of nucleic acids, as co-enzymes in biochemical pathways, and as sources of chemical energy. Nucleotides, nucleosides, oligonucleotides, oligodeoxynucleotides, and nucleobases [42-54], DNA fragments [55], and DNA and RNA [56] were recently analyzed via IPC. The potential of ionic liquids as ionic modifiers for the analysis of nucleic compounds was recently demonstrated [57]. 

There are two cation-binding sites per subunit, classified n and n.2. The nj site is a structural site, which may involve the reorientation of a glutamate carboxyl group. Metals bind first at this site. The ni site is the catalytic site and may bind metal or metal-nucleotide. Co and Cr can be incorporated into the nj metal-binding sites in un-adenylylated glutamine synthetase from E. co/i. Both derivatives were inactive, but were able to bind Mn " at the TI2 site. Comparison of the quaternary enzyme-Cr -Mn"-ADP (which shows spin-spin interaction between the two metal centres) with enzyme-Co -Mn -ADP leads to an estimate of the distance between n, and TI2 sites of 7 2 A. 

Additionally, as nucleosides and nucleotides they act as hormones and nenrotransmitters and are present in some co-enzymes. The interconversion of mono-, di- and triphosphate esters of nncleosides is at the heart of energy transfer in many metabolic systems and is also involved in intraceUnlar signalling. This central biological importance, together with medicinal chemists search for anti-tnmonr and anti-viral (particularly anti-AIDS) agents, have resulted in a rapid expansion of purine chemistry (33.6.3). 

Chromium(III) is oxophilic and can occupy sites in nucleotide complexes similar to those bound by Mg. Since Cr -nucleotide complexes are relatively inert, however, they do not support the phosphoryl transfer chemistry catalyzed by Mg in polymerases or other nucleotide-dependent enzymes. Thus, Cr -nucleotide complexes have been used to study structure and mechanism, particularly in polymerases. As one example, a co-crystal of DNA polymerase /3 with Cr -dTTP substrate shows Cr occupying one site in the two metal binding active site as a replacement of Mgii 44 structure, Cr binds to the /3,7-phosphate oxygens of the 5 -dTTP substrate. 

Plants synthesize natural rubber through what is known as activated acetic acid, CH3—CO—S—(CoA), the acetic acid thioester of the co-enzyme A (acetyl-CoA). Dimerization first gives acetyl-CoA and then, by a further addition reaction, jS-hydroxy-jS-methyl glutaryl-CoA, which is converted by the enzymatically reduced triphosphopyrridine nucleotide (TPNH)... 

In particular, 4-aminocinnolines prepared in this manner have often synthesized to compete for nucleotide co-factors in kinases and phosphodiesterases. " Thus 4-cinnolones have been used as key intermediates in the synthesis of inhibitors of these families of enzymes. 

Biologically active cinnolines are not limited to inhibitors of enzymes that require nucleotide co-factors, however. The cinnoline ring has recently been used in the synthesis of cannabinoid receptor ligands, such as 14, antimalarial agents (15), and herbicides (16). ... 

The final steps of pyrimidine biosynthesis novo which are catalyzed by two sequential enzymes, orotate phosphoribosyltransfer-ase (OPRT) and orotidylic decarboxylase (ODC), involve the PP-ribose P dependent conversion of orotic acid to orotidine-5 -monophosphate (OMP) followed by decarboxylation at the 7 position to form uridine 5 -monophosphate (UMP) (Fig. 1). UMP is then utilized further in the synthesis of nucleic acids and co-enzymes. Defects at this site in this metabolic pathway are important for they can result in "pyrimidine starvation" from depletion of the intracellular pool of pyrimidine nucleotides. In man the rare genetic disease, orotic aciduria, involves a deficiency of both OPRT and ODC (Type 1) (Smith, Sullivan and Huguley, 1961) or, less commonly, only ODC (Type II) (Fox, 0 Sullivan and Firken, 1969). 

Further work on the mode of formation of the phenylpropanoid precursors of lignin in higher plants has also been published. Confirmatory observations on the stereochemical mode of action of tyrosine ammonia lyase have been made and a review of the biochemical properties of phenylalanine ammonia lyase has been compiled by Towers and Camm . Zenk and his group . using a cell free system from cambial tissue of Salix alba and a cell free preparation from phytotron grown Forsythia species, have demonstrated for the first time the reduction of ferulate (7) to coniferyl alcohol (8) in a higher plant. The conversion is dependent on ATP, co-enzyme A and reduced pyridine nucleotides and Zenk has formulated the reaction sequence as shown below (7 - 8). 

Pyridine proteins, conjugates of pyridine nucleotides cozymase (co-enzyme I, or co-dehydrogenase I), co-enzyme II (codehydrogenase II). 

Co-enzyme I is a diphospho-pyridine nucleotide of adenine. Co-enzyme II (co-zymase) is a triphospho-pyridine nucleotide of adenine. Both co-enzymes act as hydrogen carriers in respiration (pp. 259, 330). The co-enzyme of D-amino acid oxidase is a diphospho-riboflavin nucleotide of adenine. 

Hydrolases represent a significant class of therapeutic enzymes [Enzyme Commission (EC) 3.1—3.11] (14) (Table 1). Another group of enzymes with pharmacological uses has budt-ia cofactors, eg, in the form of pyridoxal phosphate, flavin nucleotides, or zinc (15). The synthases, and other multisubstrate enzymes that require high energy phosphates, are seldom available for use as dmgs because the required co-substrates are either absent from the extracellular space or are present ia prohibitively low coaceatratioas. 

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