INOSINE MONOPHOSPHATE DEHYDROGENASE in .NET framework

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INOSINE MONOPHOSPHATE DEHYDROGENASE
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H2O IMP
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IMP Dehydrogenase NADH + H H2O Glutamine
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NAD GTP Aspartate
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ATP GMP synthetase AMP + PPi
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GDP + Pi Adenylosuccinate synthetase Adenylosuccinate Adenylosuccinate lyase Fumarate AMP
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Glutamate GMP GDP GTP
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FIGURE 8.4
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Conversion of IMP to GTP showing the role of IMPDH in GTP biosynthesis.
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formation of NADH, which absorbs at 340 nm (discussed in Section 8.4.5 with the example of uorovinylinosine). IMPDH has received considerable interest in recent years as an important target enzyme for cancer and antiviral therapies.19 32 In support of this is the observation that compounds that are potent inhibitors of IMPDH as their monophosphates (Figure 8.5), such as ribavirin, tiazofurin,
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O N O O P O O N O OH OH N NH2 O O P O O N N O OH OH O NH2 OH O O P O O N N O OH OH O NH2
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Ribavirin MP Ki = 0.1 M
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O N O O P O O N O OH OH
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Bredinin MP (Mizoribine MP) Ki = 0.5 nM
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O NH NH2 O O P O O N N O OH OH N
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EICAR MP K i = 16
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3-Deazaguanosine MP K i = 9
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2-Vinylinosine MP K i = 4
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FIGURE 8.5 and 39).
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Examples of some inhibitors of IMPDH (Ki values cited in Refs. 15,36,37,
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IMPDH INHIBITORS: DISCOVERY OF ANTIVIRAL AGENTS AGAINST EMERGING DISEASES
3-deazaguanosine, bredinin (mizoribine), and 2-vinylinosine, have all shown broad-spectrum antiviral activity against a number of viruses including the vaccinia virus.24,31,33 39 Inhibitors of IMPDH may also be of interest as antiviral agents for loviruses and other viruses that cause hemorrhagic fevers. Other support for using the IMPDH approach to drug discovery particularly against highly pathogenic RNA viruses comes from the suggestion that a common trait of many RNA viruses is a high frequency of mutation and a susceptibility to the phenomenon of error catastrophe.40 43 Indeed, it has been suggested that animal RNA viruses maintain themselves on the borderline of error catastrophe.40 Thus, it is of interest that the IMPDH inhibitor, ribavirin, produced positive responses when used in combination with interferon-a against chronic hepatitis C when patients did not respond to interferon alone.44 46 It has also been suggested that in the case of the poliovirus and perhaps other RNA viruses, ribavirin may have a lethal mutagenic effect following its incorporation (via its triphosphate) into the viral genome catalyzed by the viral RNA-dependent RNA polymerase41,42. The result is to force the RNA viruses into a lethal accumulation of errors, which are augmented by reduction of GTP pools caused by the inhibition of IMPDH by ribavirin monophosphate.47 The reason for this is that the decrease in the cellular GTP pools is likely to increase the frequency of incorporation of ribavirin triphosphate incorporation as a mutagenic GTP analogue. The mechanism of the biochemical conversion of IMP to XMP catalyzed by IMPDH15 18 involves interaction of the enzyme (Cys 331) and coenzyme (NAD ) at the 2-position of IMP (Figure 8.6). It appears that the enzyme actually binds covalently at the 2-position of IMP through the sulfhydryl group of Cys 331. This is
O HN N HN O N O
NADH
Enz-S
Enz-S
N H H
Enz-S
O H H
Ribose-5 -P
Ribose-5 -P
Ribose-5 -P
B: B:
E + IMP
E-IMP
E-XMP
O HN O N HN HO
O N HN
Enz-S
Ribose-5 -P
Enz-S
Ribose-5 -P
Ribose-5 -P
E-XMP E + XMP
FIGURE 8.6 Mechanism of the reaction catalyzed by IMPDH.15
INOSINE MONOPHOSPHATE DEHYDROGENASE
FIGURE 8.7 Ribbon diagram of IMPDH II with bound IMP.53 (Adapted with permission from Journal of Applied Crystallography.)
FIGURE 8.8 X-ray structure of the ternary complex of the human Type II IMPDH with 6-chloropurine riboside 50 -monophosphate and nicontinamide adenine dinucleotide.56 (Reproduced with permission from the Protein Data Bank.) (See insert for color representation.)
IMPDH INHIBITORS: DISCOVERY OF ANTIVIRAL AGENTS AGAINST EMERGING DISEASES
followed by an oxidation step (hydride abstraction) at the 2-position involving NAD followed by hydration at this position and ejection of the enzyme. All of the chemistry taking place at the 2-position is of signi cance in the design of inhibitors of IMPDH and this has has been the focus of some of our work in this area. The human enzyme exists in two isoforms, Type I (expressed in normal cells) and Type II (predominates in neoplastic and fast replicating cells).48,49 Human Type I and II enzymes have been cloned and expressed in Escherichia coli.50 There has been much renewed interest in this enzyme in the last few years (e.g. see Refs. 29, 36, 38, 39, 51, and 52). Several recent crystal structures of IMPDH have been determined (Figures 8.7 and 8.8).53 56 In our laboratory, we have isolated and studied bacterial IMPDH (from E. coli B3 strain) and human recombinant IMPDH II.39
8.4 INHIBITORS OF IMPDH WITH ACTIVITY AGAINST VIRUSES OF EMERGING DISEASES AND BIOTERRORISM THREATS Of the potential weapons of bioterrorism, smallpox poses one of the greatest threats. There are a number of compounds that are known to be inhibitors of orthopoxviruses and some of their biochemical mechanisms of action are as follows: inhibition of inosine monophosphate dehydrogenase (IMPDH) [e.g., ribavirin, ethynylimidazolecarboxamide riboside (EICAR), uoroimidazolecarboxamide riboside (FICAR), tiazofurin and selenazole, 2-vinylinosine], S-adenosylhomocysteine hydrolase (SAHase) inhibitors (e.g., neplanocin and its analogues, 50 -noraristeromycin and its analogues), thymidylate synthase inhibitors [e.g., (E)-5-(2-bromovinyl)deoxyuridine (BVDU)], and viral DNA synthesis inhibitors [e.g., cidofovir (HPMPC)].31,34,57 61 A few of these compounds are inhibitors of orthopox virus replication by more than one mechanism of action. Representative examples are discussed below. 8.4.1 Ribavirin