Thiazole-4-carboxamide adenine dinucleotide (TAD). Analogs stable to phosphodiesterase hydrolysis

Márquez, Víctor E.; Tseng, Christopher K. H.; Gebeyehu, Gulilat; Cooney, David A.; Ahluwalia, Gurpreet S.; Kelley, James A.; Dalal, Maha; Fuller, Richard W.; Wilson, Yvonne A.; Johns, David G.

doi:10.1021/jm00159a027

Cited by 44 publications

(36 citation statements)

References 4 publications

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“…This observation suggests that CH 2 -TAD also binds to E-XMP*. The K ii of CH 2 -TAD ϭ 1.0 M is approximately 20-fold greater than that of mammalian IMPDHs (36), further demonstrating a difference in the dinucleotide sites of microbial and mammalian IMPDHs.…”

Section: Resultsmentioning

confidence: 90%

Expression, Purification, and Characterization of Inosine 5′-Monophosphate Dehydrogenase from Borrelia burgdorferi

Zhou¹,

Cahoon²,

Rosa³

et al. 1997

Journal of Biological Chemistry

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Inosine 5-monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in de novo guanine nucleotide biosynthesis. IMPDH converts IMP to xanthosine 5-monophosphate with concomitant conversion of NAD ؉ to NADH. All IMPDHs characterized to date contain a 130-residue "subdomain" that extends from an N-terminal loop of the ␣/␤ barrel domain. Inosine 5Ј-monophosphate dehydrogenase catalyzes the conversion of IMP to XMP 1 with the concomitant reduction of NAD to NADH. This reaction is the rate-limiting step in guanine nucleotide biosynthesis, and is therefore a target for numerous chemotherapeutic agents (1). IMPDH inhibitors are used clinically in antiviral (ribavirin) and immunosuppressive therapies (mycophenolate mofetil and mizoribine) (2-4). In addition, IMPDH inhibitors have anti-tumor and antibiotic activity (5, 6). Mammalian and bacterial IMPDHs have significantly different kinetic properties and inhibitor sensitivities, which suggests that species-specific IMPDH inhibitors can be developed that will be useful in treating bacterial and parasitic infections (7-9). Indeed, many studies have shown that purine metabolism plays an important role in bacterial virulence (10 -13).The spirochete Borrelia burgdorferi is the causative agent of Lyme disease (14). This disease is transmitted by ticks of the Ixodes ricinus complex and is found worldwide. The genes encoding GMP synthase (guaA) and IMPDH (guaB) are located on a 26-kb circular plasmid (cp26) in B. burgdorferi (15). Genes carried by plasmids generally confer selective advantage in a particular environmental niche. The unique plasmid location of these housekeeping genes in B. burgdorferi may be related to their role in the transmission cycle between ticks and mammals. In ticks, guanine is the major nitrogenous waste product and therefore accumulates to high levels. However, in mammals, purine levels are low and limiting for bacterial growth. Therefore expression of the gua genes would be unnecessary for the survival of B. burgdorferi in ticks, but critical for survival in a mammalian host. Consistent with an adaptive role of cp26 in the mammalian environment, the gua genes are linked with ospC, which is induced during tick feeding. ospC encodes a protein that appears on the outer surface of the spirochete immediately preceding transmission to the mammal (16).The identity of B. burgdorferi guaA was confirmed by complementation of GMP synthase-deficient Escherichia coli (15); however, the guaB homolog did not complement IMPDHdeficient E. coli. The failure to observe complementation by B. burgdorferi guaB most likely results from incompatible promoters or unstable protein. Alternatively, the guaB homolog may not encode an active IMPDH. Indeed, the guaB homolog, with a predicted molecular mass of 44 kDa, is 10 kDa smaller than typical IMPDHs. This difference in size results from the loss of 130 residues (residues 110 -244, Chinese hamster IMPDH numbering) in the middle of IMPDH. These residues have been replaced with 50 residues of unrelated sequence (15).The cry...

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Section: Resultsmentioning

confidence: 90%

Expression, Purification, and Characterization of Inosine 5′-Monophosphate Dehydrogenase from Borrelia burgdorferi

Zhou¹,

Cahoon²,

Rosa³

et al. 1997

Journal of Biological Chemistry

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“…␤-CH 2 -TAD is structurally similar to TAD (Fig. 1b) but is resistant to the reverse pyrophosphorylase reaction catalyzed by NMNAT (16). The active site of the enzyme appears to accommodate ␤-CH 2 -TAD easily; the bulkier sulfur atom on the thiazole ring is cis to the furanose oxygen O1Ј and is pointed toward the solvent.…”

Section: Resultsmentioning

confidence: 93%

Structure of Human Nicotinamide/Nicotinic Acid Mononucleotide Adenylyltransferase

Zhou

Kurnasov

Tomchick

et al. 2002

Journal of Biological Chemistry

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Nicotinamide/nicotinate mononucleotide (NMN/ NaMN)adenylyltransferase (NMNAT) is an indispensable enzyme in the biosynthesis of NAD؉ and NADP ؉ . Human NMNAT displays unique dual substrate specificity toward both NMN and NaMN, thus flexible in participating in both de novo and salvage pathways of NAD synthesis. Human NMNAT also catalyzes the ratelimiting step of the metabolic conversion of the anticancer agent tiazofurin to its active form tiazofurin adenine dinucleotide (TAD). The tiazofurin resistance is mainly associated with the low NMNAT activity in the cell. We have solved the crystal structures of human NMNAT in complex with NAD, deamido-NAD, and a non-hydrolyzable TAD analogue ␤-CH 2 -TAD. These complex structures delineate the broad substrate specificity of the enzyme toward both NMN and NaMN and reveal the structural mechanism for adenylation of tiazofurin nucleotide. The crystal structure of human NMNAT also shows that it forms a barrel-like hexamer with the predicted nuclear localization signal sequence located on the outside surface of the barrel, supporting its functional role of interacting with the nuclear transporting proteins. The results from the analytical ultracentrifugation studies are consistent with the formation of a hexamer in solution under certain conditions. Nicotinamide/nicotinic acid mononucleotide (NMN/NaMN) 1 adenylyltransferase (NMNAT) is an indispensable enzyme in both de novo and salvage pathways of NAD biosynthesis (1, 2) (Fig. 1a). In human, the de novo NAD biosynthesis proceeds via several enzymatic steps to transform tryptophan into NaMN, which is then converted into deamido-NAD (NaAD) via the action of the ubiquitous enzyme NMNAT, and into NAD by means of NAD synthetase (2). Alternatively, the nicotinamide or nicotinamide ribose from degradation of NAD or from the extracellular medium can be re-used and adenylated by NMNAT to form NAD directly, potentially bypassing the last amidation step catalyzed by NAD synthetase (Fig. 1a). Human NMNAT displays unique dual substrate specificity toward both NMN and NaMN (3, 4) and is thus capable of participating in both de novo and salvage pathways of NAD generation.In addition to the fundamental role as coenzyme in hundreds of oxidation-reduction reactions throughout the cell, NAD can also be used as a substrate for the modification of a variety of nuclear proteins by ADP-ribosyltransferases (5, 6) and for the repair of DNA by DNA ligase in bacteria (7,8). The formation of protein-coupled poly(ADP-ribose) relaxes the chromatin structure and facilitates DNA regulatory and repair events under conditions of DNA damage. Recently, several NAD derivatives such as cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate have been reported to be potent intracellular calcium-mobilizing agents participating in calcium-dependent signaling pathways (5, 9). In some situations these processes may significantly deplete the cellular NAD pool which, coupled with a decrease in ATP production, could potentially lead to a cellular energy cris...

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“…Tiazofurin resistance can result from decreases in uptake and/or NMN adenyltransferase as well as by increases in the amount of phosphodiesterase. These observations prompted the development of non-hydrolyzable analogs of TAD 241,242. Beta-methylene TAD inhibits hIMPDH2 with equivalent potency to TAD, while the potency of beta-difluoromethylene-TAD is decreased by a factor of 3.…”

Section: Inhibitors Of Impdhmentioning

confidence: 99%

IMP Dehydrogenase: Structure, Mechanism, and Inhibition

2009

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Thiazole-4-carboxamide adenine dinucleotide (TAD). Analogs stable to phosphodiesterase hydrolysis

Cited by 44 publications

References 4 publications

Expression, Purification, and Characterization of Inosine 5′-Monophosphate Dehydrogenase from Borrelia burgdorferi

Expression, Purification, and Characterization of Inosine 5′-Monophosphate Dehydrogenase from Borrelia burgdorferi

Structure of Human Nicotinamide/Nicotinic Acid Mononucleotide Adenylyltransferase

IMP Dehydrogenase: Structure, Mechanism, and Inhibition

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