Metabolism of cyclic ADP-ribose: A new role for NAD+ glycohydrolases

Ziegler, Mathias; Jorcke, Dierk; Schweiger, Manfred

doi:10.1007/3-540-61992-5_6

Cited by 6 publications

(10 citation statements)

References 160 publications

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“…It is now clear that an accepted nucleophile is the N 1 nitrogen of the adenine moiety and the reaction then leads to the formation of cADPR. This reaction mechanism also provides a rationale for the observation that cADPR is readily hydrolyzed to ADP‐ribose by the synthesizing enzymes [101–105] (Fig. 4, reaction 3).…”

mentioning

confidence: 94%

“…Owing to their newly recognized potential capabilities, many of these enzymes have been tested for ADP‐ribosyl cyclase activity. So far, only one enzyme of several studied, the NAD + glycohydrolase from Neurospora crassa , has failed to produce cADPR [103,111]; it probably hydrolyzes NAD + by a mechanism distinct from that described above. ADP‐ribosyl cyclases have been found in a variety of organisms including prokaryotes and eukaryotes ([7], reviewed in [94,103]).…”

mentioning

confidence: 99%

“…So far, only one enzyme of several studied, the NAD + glycohydrolase from Neurospora crassa , has failed to produce cADPR [103,111]; it probably hydrolyzes NAD + by a mechanism distinct from that described above. ADP‐ribosyl cyclases have been found in a variety of organisms including prokaryotes and eukaryotes ([7], reviewed in [94,103]). It seems, therefore, that these enzymes and hence calcium regulation via cADPR have been conserved during evolution.…”

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confidence: 99%

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New functions of a long‐known molecule

Ziegler

2000

European Journal of Biochemistry

260

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Over the past decades, the pyridine nucleotides have been established as important molecules in signaling pathways, besides their well known function in energy transduction. Similarly to another molecule carrying such dual functions, ATP, NAD(P) 1 may serve as substrate for covalent protein modification or as precursor of biologically active compounds.Protein modification is catalyzed by ADP-ribosyl transferases that attach the ADP-ribose moiety of NAD 1 to specific amino-acid residues of the acceptor proteins. For a number of ADP ribosylation reactions the specific transferases and their target proteins have been identified. As a result of the modification, the biological activity of the acceptor proteins may be severely changed. The cell nucleus contains enzymes catalyzing the transfer of ADP-ribose polymers (polyADP-ribose) onto the acceptor proteins. The best known enzyme of this type is poly(ADP-ribose) polymerase 1 (PARP1), which has been implicated in the regulation of several important processes including DNA repair, transcription, apoptosis, neoplastic transformation and others.The second group of reactions leads to the synthesis of an unusual cyclic nucleotide, cyclic ADP-ribose (cADPR). Moreover, the enzymes catalyzing this reaction may also replace the nicotinamide of NADP 1 by nicotinic acid resulting in the synthesis of nicotinic acid adenine dinucleotide phosphate (NAADP 1 ). Both cADPR and NAADP 1 have been reported to be potent intracellular calcium-mobilizing agents. In concert with inositol 1,4,5-trisphosphate, they participate in cytosolic calcium regulation by releasing calcium from intracellular stores.

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confidence: 94%

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confidence: 99%

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New functions of a long‐known molecule

Ziegler

2000

European Journal of Biochemistry

260

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“…ADP-ribosylation in proteins has been shown to be responsible for many posttranslational modifications, such as in apoptosis (Bricker et al, 2005), cell signaling (Ziegler et al, 1997), DNA repair (Althaus et al, 1982), and gene regulation (Ryu et al, 2015). Such modification often results in the inactivation of target proteins (Haag and Koch-Nolte, 1997).…”

Section: Adp-ribosyltransferasementioning

confidence: 99%

Going Beyond Common Drug Metabolizing Enzymes: Case Studies of Biotransformation Involving Aldehyde Oxidase, -Glutamyl Transpeptidase, Cathepsin B, Flavin-Containing Monooxygenase, and ADP-Ribosyltransferase

Pw¹,

Zhang²,

Js³

et al. 2016

Drug Metabolism and Disposition

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The significant roles that cytochrome P450 (P450) and UDPglucuronosyl transferase (UGT) enzymes play in drug discovery cannot be ignored, and these enzyme systems are commonly examined during drug optimization using liver microsomes or hepatocytes. At the same time, other drug-metabolizing enzymes have a role in the metabolism of drugs and can lead to challenges in drug optimization that could be mitigated if the contributions of these enzymes were better understood. We present examples (mostly from Genentech) of five different non-P450 and non-UGT enzymes that contribute to the metabolic clearance or bioactivation of drugs and drug candidates. Aldehyde oxidase mediates a unique amide hydrolysis of ,7-tetrahydro-1-benzothiophene-2-carboxamide), leading to high clearance of the drug. Likewise, the rodent-specific ribose conjugation by ADP-ribosyltransferase leads to high clearance of an interleukin-2-inducible T-cell kinase inhibitor. Metabolic reactions by flavin-containing monooxygenases (FMO) are easily mistaken for P450-mediated metabolism such as oxidative defluorination of 4-fluoro-N-methylaniline by FMO. Gamma-glutamyl transpeptidase is involved in the initial hydrolysis of glutathione metabolites, leading to formation of proximate toxins and nephrotoxicity, as is observed with cisplatin in the clinic, or renal toxicity, as is observed with efavirenz in rodents. Finally, cathepsin B is a lysosomal enzyme that is highly expressed in human tumors and has been targeted to release potent cytotoxins, as in the case of brentuximab vedotin. These examples of non-P450-and non-UGT-mediated metabolism show that a more complete understanding of drug metabolizing enzymes allows for better insight into the fate of drugs and improved design strategies of molecules in drug discovery.

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“…On the other side, an important fraction of cytosolic calcium is permanently taken up by the mitochondria (to maintain the activity of redox enzymes, hence the level of oxidative phosphorylation) and by the nucleus, involving an ATP-ase and inositoltetraphosphate [7]. As an intracellular messenger almost indispensable to all forms of cellular response, cytosolic calcium increases during cell activation as a result of the intensification of both the influx and the release from the endoplasmic reticulum, involving IP 3 and from mitochondria, involving cyclic ADP-ribose [8]. In addition, mutations in genes encoding presenilins proved to sensitize neurons to apoptosis by different mechanisms e.g.…”

Section: Cognitive Acquisitions In Functional Genomicsmentioning

confidence: 99%

From molecular genetics to functional genomics and physiome

Haulică

2002

J Cellular Molecular Medi

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Metabolism of cyclic ADP-ribose: A new role for NAD+ glycohydrolases

Cited by 6 publications

References 160 publications

New functions of a long‐known molecule

New functions of a long‐known molecule

Going Beyond Common Drug Metabolizing Enzymes: Case Studies of Biotransformation Involving Aldehyde Oxidase, -Glutamyl Transpeptidase, Cathepsin B, Flavin-Containing Monooxygenase, and ADP-Ribosyltransferase

From molecular genetics to functional genomics and physiome

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