Nuclear Magnetic Resonance and Molecular Modeling Study on Mycophenolic Acid:  Implications for Binding to Inosine Monophosphate Dehydrogenase

Makara, Gergely M.; Keserü, György M.; Kajtár-Peredy, Mária; Anderson, Wayne K.

doi:10.1021/jm950600m

Cited by 16 publications

(12 citation statements)

References 35 publications

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“…The other known compounds isolated from P. kongii including pebrolide (Mccorkindale et al 1981) ( 2 ), 1-deoxypebrolide (Mccorkindale et al 1981) ( 3 ), asperphenamate (McCorkindale et al 1978) ( 4 ), N-benzoyl-phenylalaninol (McCorkindale et al 1978) ( 8 ), orsellinic acid (Fang et al 2012) ( 9 ), mycophenolic acid (Makara et al 1996) ( 10 ), and 5, 7-dihydroxy-4-methylphthalide (Fujimoto et al 1999) ( 11 ), and the other known compounds isolated from P. brasilianum including 12, 13-dihydroxyfumitremorgin C (Inokoshi et al 2013) ( 12 ), verruculogen (Afiyatullov et al 2004) ( 13 ), viridicatumtoxin (Inokoshi et al 2013) ( 14 ), dehydroaustin (Hayashi et al 1994) ( 15 ), austinolide (Lo et al 2012) ( 16 ), neoaustin (Hayashi et al 1994) ( 17 ), brasiliamide A (Fujita et al 2002) ( 18 ), brasiliamide C (Fujita & Hayashi 2004) ( 19 ), and aspterric acid (Shimada et al 2002) ( 20 ), were determined by comparison of those reported spectroscopic data. Among these, aspterric acid is reported from P. brasilianum for the first time.…”

Section: Resultsmentioning

confidence: 99%

Chemical diversity from the Tibetan Plateau fungi Penicillium kongii and P. brasilianum

Liu

et al. 2017

Mycology

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Two new secondary metabolites, kongiilines A and B (1, 7), and two asperphenamate derivatives, asperphenamates B and C (5–6), together with 16 known compounds (2–4, 8–20), were isolated from Tibetan Plateau fungi Penicillium kongii and Penicillium brasilianum. This is the first report on asperphenamates B and C as naturally occurring compounds, and that aspterric acid is isolated from P. brasilianum for the first time. Their structures were elucidated by different spectroscopic techniques including high-resolution electrospray ionisation mass spectrum, 1D nuclear magnetic resonance (NMR), and 2D NMR as well as electronic circular dichroism. Compounds 4, 5, and 10 exhibited cytotoxicity activities against human colon carcinoma HCT116 cell line with IC50 values of 88.16, 77.68, and 36.92 μM, respectively. Fungi from Tibetan Plateau represent important and rich resources for the investigation of new chemicals.

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Section: Resultsmentioning

confidence: 99%

Chemical diversity from the Tibetan Plateau fungi Penicillium kongii and P. brasilianum

Liu

et al. 2017

Mycology

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“…The hexanoic side chain has a restricted conformation due to the presence of the C7 hydroxy and C5 methoxy groups on the aromatic ring and the E geometry of the side-chain double bond. NMR analysis of apo-MPA in solution suggested that the most likely stable solution configuration involves a bent conformation with the carboxyl group bent toward the aromatic ring rather than being in an extended conformation (although C4‘ to the end of the chain is the most conformationally flexible region) …”

Section: Resultsmentioning

confidence: 99%

“…The protons of the C5 methoxy group (5Me) are not too perturbed suggesting this group is not close to the metal ion despite the apparent closeness to C1‘ and C2‘. Makara et al show that the methoxy group is forced out of the plane of the aromatic ring as a result of interactions with the neighboring methyl and hexanoic acid groups . In apo-MPA the NMR derived distance between the C5 methoxy group and the C1‘ and C2‘ protons is 4.0 Å and 3.3 Å, respectively.…”

Section: Resultsmentioning

confidence: 99%

Spectroscopic Characterization of Copper(II) Binding to the Immunosuppressive Drug Mycophenolic Acid

et al. 2006

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Mycophenolic acid (MPA) is a drug that has found widespread use as an immunosuppressive agent which limits rejection of transplanted organs. Optimal use of this drug is hampered by gastrointestinal side effects which can range in severity. One mechanism by which MPA causes gastropathy may involve a direct interaction between the drug and gastric phospholipids. To combat this interaction we have investigated the potential of MPA to coordinate Cu(II), a metal which has been used to inhibit gastropathy associated with use of the NSAID indomethacin. Using a range of spectroscopic techniques we show that Cu(II) is coordinated to two MPA molecules via carboxylates and, at low pH, water ligands. The copper complex formed is stable in solution as assessed by mass spectrometry and 1H NMR diffusion experiments. Competition studies with glycine and albumin indicate that the copper-MPA complex will release Cu(II) to amino acids and proteins thereby allowing free MPA to be transported to its site of action. Transfer to serum albumin proceeds via a Cu(MPA)(albumin) ternary complex. These results raise the possibility that copper complexes of MPA may be useful in a therapeutic situation.

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“…This orientation is stabilized by an intramolecular electrostatic interaction between the ribose oxygen and the partially positively charged S/Se atoms (23,24). Modeling studies on MPA, another potent IMPDH inhibitor that binds to the nicotinamide portion of the dinucleotide binding site (63), suggested that MPA binds by adopting an anti-like conformation (64). Thus it appears that the nicotinamide conformation of IMPDH-bound NADH is related to the unusually high affinity of IMPDH for nicotinamide-substituted analogues such as TAD and SAD which lack the positive charge of the NAD + nicotinamide ring and thus are best described as NADH analogues rather than NAD + analogues (60)(61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

The Conformation of NADH Bound to Inosine 5‘-Monophosphate Dehydrogenase Determined by Transferred Nuclear Overhauser Effect Spectroscopy

1998

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Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the oxidation of inosine 5-monophosphate (IMP) to xanthosine 5'-monophosphate (XMP). The reaction proceeds with concomitant conversion of NAD+ to NADH and is the rate-limiting step in the de novo biosynthesis of guanosine nucleotides. IMPDH is a target for numerous chemotherapeutic agents. The conformations of enzyme-bound substrates, enzyme-bound products and enzyme-bound ligands in general, are of interest for the understanding of the catalytic mechanism of the enzyme and the design of new inhibitors. Although several of the chemotherapeutic inhibitors of IMPDH are NAD+ or NADH analogues, no structural data for IMPDH-bound NAD+ (or NADH) are available. In the present work, we have used transferred nuclear Overhauser effect spectroscopy (TRNOESY) to determine the conformation of NADH bound to the active site of human type II IMPDH (IMPDH-h2). The inter-proton distances determined from TRNOESY data indicate that NADH binds to the enzyme active site in an overall extended conformation. The adenosine moiety and the nicotinamide riboside moiety are both in the anti conformation about the glycosidic bond, and both ribose rings are in approximately C4'-exo conformations. The nicotinamide amide group was found to be in a cis conformation. The anti conformation of the nicotinamide riboside moiety is in accord with the preferred conformations of several potent and selective dinucleotide inhibitors and is consistent with that implied by the stereospecificity of hydride transfer in the enzymatic reaction. The implications of this conformation for the catalytic mechanism of IMPDH-h2 are discussed.

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Nuclear Magnetic Resonance and Molecular Modeling Study on Mycophenolic Acid: Implications for Binding to Inosine Monophosphate Dehydrogenase

Cited by 16 publications

References 35 publications

Chemical diversity from the Tibetan Plateau fungi Penicillium kongii and P. brasilianum

Chemical diversity from the Tibetan Plateau fungi Penicillium kongii and P. brasilianum

Spectroscopic Characterization of Copper(II) Binding to the Immunosuppressive Drug Mycophenolic Acid

The Conformation of NADH Bound to Inosine 5‘-Monophosphate Dehydrogenase Determined by Transferred Nuclear Overhauser Effect Spectroscopy

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