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Carbohydrate Chains: Enzymatic and Chemical Synthesis This article was originally published in the Encyclopedia of Biological Chemistry published by Elsevier, and the attached copy is provided by Elsevier for the author's benefit and for the benefit of the author's institution, for non-commercial research and educational use including without limitation use in instruction at your institution, sending it to specific colleagues who you know, and providing a copy to your institution’s administrator. All other uses, reproduction and distribution, including without limitation commercial reprints, selling or licensing copies or access, or posting on open internet sites, your personal or institution’s website or repository, are prohibited. For exceptions, permission may be sought for such use through Elsevier's permissions site at: http://www.elsevier.com/locate/permissionusematerial Bogan K.L., and Brenner C. (2013) Biochemistry: Niacin/NAD(P). In: Lennarz W.J. and Lane M.D. (eds.) The Encyclopedia of Biological Chemistry, vol. 1, pp. 172-178. Waltham, MA: Academic Press. © 2013 Elsevier Inc. All rights reserved. Author's personal copy Biochemistry: Niacin/NAD(P) K L Bogan and C Brenner, The University of Iowa, Iowa City, IA, USA ã 2013 Elsevier Inc. All rights reserved. Glossary Pellagra Niacin-deficient nutritional condition. þ þ + Nicotinoproteins NAD - or NADP -dependent Poly(ADPribose) polymerase NAD -dependent oxidoreductases that bind the coenzymes tightly as enzyme that forms protein linked or unlinked chains prosthetic groups. of ADPribose. þ Oxidoreductase A coenzyme-dependent hydride Sirtuin NAD -dependent protein lysine deacetylase transfer enzyme. related to yeast Sir2. Nicotinamide Adenine Dinucleotide History and nicotinamide riboside (NR). These water-soluble vitamins are þ Structure NAD breakdown products and metabolites that are trans- ported systemically; these are available in the diet (Figure 2(a)). þ Nicotinamide adenine dinucleotide (NAD ) was at the center NA is utilized by the Preiss–Handler pathway, which of some of the greatest discoveries in the biological sciences in involves three enzymatic steps through nicotinic acid mono- the early twentieth century. Originally termed cozymase or nucleotide (NaMN) and nicotinic acid adenine dinucleotide codehydrogenase I and later diphosphopyridine nucleotide (NaAD). In vertebrates, Nam is utilized in two enzymatic (DPN), the activity was described in 1905 as a component of steps through nicotinamide mononucleotide (NMN). Since yeast extracts that accelerated cell-free alcoholic fermentation. Nam can be converted into NA in many bacteria by a nicoti- Arthur Harden and William Young discovered that glycolysis namidase not encoded in vertebrate genomes, Nam entry proceeded slowly until a heat-stable and dialyzable cozymase into the Preiss–Handler pathway in vertebrates is thought þ fraction was added, which we now know contained NAD , to depend on bacterial nicotinamidase in the gut. NR can be þ þ þ adenosine triphosphate (ATP), and Mg2 . The NAD compo- converted into two steps to NAD through NMN, or can be þ nent was later purified by Harden and Hans von Euler. In 1936, converted into NAD via splitting the nucleoside followed by þ the structure of NAD was determined independently by Otto Nam salvage. Specific transporters have been identified for Warburg and von Euler, and a role in oxidative metabolism was the uptake of NA and NR, but not Nam or nicotinic acid þ defined. Codehydrogenase II was found to be a triphosphopyr- riboside (NAR), an NAD metabolite that can also be utilized idine dinucleotide, that is, nicotinamide adenine dinucleotide byyeastathighdoses. þ þ þ phosphate (NADP ). Two salvageable precursors of NAD , Most organisms synthesize NAD from either tryptophan nicotinic acid (NA) and nicotinamide (Nam), were identified or aspartic acid. De novo synthesis nearly always proceeds by Conrad Elvehjem in a search for non protein fractions from through quinolinic acid (QA) and NaMN, at which point þ the liver that would reverse black spots on the tongues of dogs, NAD is produced by the last two enzymes of the Preiss– an induced nutritional deficiency similar to pellagra, which was Handler pathway (Figure 3). þ an epidemic in the American South in the early 1900s. Later, the The phosphorylated forms of NAD are also generated by þ þ basis for both de novo synthesis of NAD from amino acids and specific enzyme activities (Figure 2(b)). NADP is generated þ þ þ salvage synthesis of NAD was worked out. NA and Nam were from NAD by NAD kinase (NADK). In yeast, a mitochon- collectively termed ‘niacins’. The broad use of niacin supple- drial NADH kinase generates NADPH from NADH. In addi- mentation has virtually eliminated pellagra. tion, in bacteria and in animal mitochondria, the proton þ NAD is so termed because it consists of a Nam nucleotide, translocating, membrane-bound NADPH transhydrogenase 0 þ þ that is, nicotinamide riboside 5 -monophosphate, joined to interconverts NADPH and NAD into NADP and NADH. the phosphate of an adenine nucleotide, that is., adenosine Thus, NADK activity is a gatekeeper of both phosphorylated 0 þ þ 5 -monophosphate. NADP is formed when a phosphate group forms of NAD , and NADPH transhydrogenase allows a cell to þ is added to the 20 position of adenosine (Figure 1). The glyco- maintain a redox balance in which NAD levels exceed NADH þ sidic linkages between bases and ribosyl moieties are b in both levels, while NADPH levels exceed those of NADP . nucleotides. The hydride-accepting moiety is the Nam base such þ þ that the plus signs on NAD and NADP refer to the oxidized, þ þ hydride-accepting forms. The overall charge of these molecules NAD and NADP in Redox Metabolism is negative because of the phosphates. Electron transfers that occur in oxidation–reduction (redox) reactions are essential to metabolism and life in all organisms. Salvage and De Novo Pathways Redox reactions are catalyzed by a large family of enzymes called ‘oxidoreductases’. The electron-donating species in a þ All dividing cells either form NAD de novo from an ami- redox reaction is referred to as the reducing agent, or reductant, þ no acid and/or resynthesize NAD from NA, Nam, and/or and the electron-accepting species is the oxidizing agent, or 172 Encyclopedia of Biological Chemistry, (2013), vol. 1, pp. 172-178 Author's personal copy Metabolism Vitamins and Hormones | Biochemistry: Niacin/NAD(P) 173 b-NAD+ b-NADH Oxidized form Reduced form NH 2 O HH O N N Nicotinamide NH2 - + :H NH2 N N N O O O O OOP OP N - - O O HO OH XO OH ADPribose ADPribose ADP NR AMP NMN X = H NAD+ X =PO2-NADP+ 3 þ þ þ Figure 1 NAD /NADH and NADP /NADPH structure. NAD is a dinucleotide consisting of a nicotinamide nucleotide, that is, nicotinamide riboside 0 0 þ X 5 -monophosphate (NMN) joined to the phosphate of an adenine nucleotide, that is, adenosine 5 -monophosphate (AMP). In NAD , the in the 0 þ X 2 position of the adenosine is an H, whereas in NADP , a phosphate group is in the position. The glycosidic linkages between bases and ribosyl þ þ moieties are b in both nucleotides. The Nam base is the hydride-accepting moiety, such that the plus signs on NAD and NADP refer to the oxidized, hydride-accepting forms. oxidant. In biological redox reactions, the movement of elec- 20-hydroxyl group of the adenine nucleotide. This site also þ trons often occurs concomitant with the loss of hydrogen. This helps to distinguish enzymes that bind NAD from those þ species is referred to as a hydride ion (:H–). that bind NADP , as this residue is uncharged in enzymes þ þ þ In NAD -dependent dehydrogenation reactions, NAD that bind NADP in order to accommodate the 20-phosphate þ þ and NADP undergo reduction of the nicotinamide ring to that takes the place of the hydroxyl. In NADP -binding form NADH and NADPH, respectively (Figure 1). In such enzymes, the phosphate interacts with a nearby arginine resi- reactions, a hydride ion is transferred to the carbon at the due instead. The phosphate-binding glycine-rich sequence þ fourth position of the nicotinamide ring of NAD (Figure 1). (GXGXXG) resides in a loop between the first a-helix and This transfer of hydride can happen in two ways. In A-type b-strand. The first and second glycines are thought to allow oxidoreductases, the hydrogen is transferred from above the important turns of the main chain in this loop. These turns plane of the nicotinamide ring to the front of the nicotinamide promote an interaction between the main chain and the þ ring (A side), while B-type oxidoreductases transfer of the atom diphosphate bridge of NAD to occur (Figure 4(b)). The occurs from below to the backside of the nicotinamide ring third glycine promotes tight packing in the nucleotide-binding þ þ þ (B side). This depends on how NAD is oriented within the domain that prohibits NADP from binding. NADP -binding nucleotide-binding domain of the enzyme. enzymes have a larger amino acid (alanine, serine, or proline) þ Oxidoreductases bind the NAD(P) dinucleotide in a struc- in the place of the glycine, which disrupts the close packing þ tural motif termed as a Rossmann fold (Figure 4(a)). The core and allows NADP to bind. Finally, the hydrophobic core, Rossman fold consists of one nucleotide-binding domain which contains six small hydrophobic amino acids, is neces- constructed from at least three b-strands flanked by two a- sary for maintaining the proper packing of the b-strands with helices (babab ), though some oxidoreductases have addi- respect to the a-helices. While these motifs form the proper tional b-strands. There are four important motifs found tertiary structure and interactions to specify binding of þ þ within the Rossmann fold: a conserved positively charged NAD versus NADP , some enzymes, such as aldose reductase, residue (Arg or Lys) at the beginning of the first b-strand, a glucose-6-phosphate dehydrogenase, and methylenetetrahy- conserved negatively charged residue (Glu or Asp) at the drofolate reductase, are exceptions to the rule, and bind both þ þ end of the second b-strand, a phosphate-binding sequence – NAD and NADP .
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