Mycophenolate Mofetil: A Report of the Consensus Panel

Shaw, Leslie M.; Sollinger, Hans W.; Halloran, Philip F.; Morris, Randall E.; Yatscoff, Randall W.; Ransom, John; Tsina, I; Keown, Paul; Holt, David W.; Lieberman, Ronald; Jaklitsch, A; Potter, Julia M.

doi:10.1097/00007691-199512000-00025

Cited by 111 publications

(54 citation statements)

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“…Typical assays contained substrate concentrations of 300 and 250 M for IMP and NAD ϩ , respectively, and 100 nM IMPDH in Buffer A. Protein concentrations were routinely determined by UV spectroscopy, using a specific molar extinction coefficient (A 278 ) of 23 ), expressed relative to IMPDH protomer concentration. Where this was complicated by other UV-absorbing species, concentrations were determined by the method of Bradford (42) using hamster IMPDH II (concentration determined as above) as the standard.…”

Section: Methodsmentioning

confidence: 99%

“…The drug has been approved in the United States and Europe for the prevention of acute rejection in kidney transplant recipients, but broader clinical use may be complicated by drug toxicity (for reports and reviews of clinical findings, see Refs. [21][22][23][24]. Therefore, with the goal of increasing drug efficacy and decreasing toxic side effects, there is great interest in characterizing the inhibition of IMPDH by MPA and other compound classes.…”

mentioning

confidence: 99%

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Conformational Changes and Stabilization of Inosine 5′-Monophosphate Dehydrogenase Associated with Ligand Binding and Inhibition by Mycophenolic Acid

Nimmesgern

Fox

Fleming

et al. 1996

Journal of Biological Chemistry

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The effects of substrate, product, and inhibitor (mycophenolic acid) binding on the conformation and stability of hamster type II inosine 5-monophosphate dehydrogenase (IMPDH) have been examined. The protein in various states of ligand occupancy was compared by analyzing susceptibility to in vitro proteolysis, the degree of binding of a hydrophobic fluorescent dye, secondary structure content as determined by far-UV circular dichroism spectra, and urea-induced denaturation curves. These analysis methods revealed consistent evidence that IMPDH undergoes a local reorganization when IMP or XMP bind. NAD ؉ produced no such effect. In fact, no evidence was found for NAD ؉ binding independently of IMP. It is proposed that IM-PDH adopts an open conformation around its nucleotide binding sites in the absence of substrates and that binding of IMP stabilizes a closed conformation that has a higher affinity for NAD ؉ . The data also suggest the enzyme remains in the closed configuration throughout the catalytic steps and then reverts to the open conformation with XMP release, thereby consummating the enzyme cycle. Mycophenolic acid inhibition appeared to impart even greater stability. We propose that localized conformational changes occur during the normal and mycophenolic acid-inhibited reaction sequences of IMPDH.Inosine 5Ј-monophosphate dehydrogenase (IMPDH; 1 EC 1.1.1.205) catalyzes the conversion of IMP to XMP, the committed step in the de novo biosynthesis of guanine nucleotides (1-4). Now partially characterized from many organisms, IMPDH is well conserved with 35% or more sequence identity from bacterial and protozoan to human proteins (5, 6). Since the enzyme appears to be necessary for cellular replication, some view it as an attractive target for anti-microbial chemotherapy; however, others have recognized further therapeutic possibilities for IMPDH inhibition.Human and hamster possess two closely related isoenzymes (designated types I and II). In both species the isoforms share 84% (of 514 residues) sequence identity (5).2 The existence of similar isoenzymes in mammals suggests a subtle distinction of roles. Many studies have shown that IMPDH activity is elevated in tumors and other actively proliferating tissues (3,4,(7)(8)(9)(10)(11)(12)(13)(14)(15). In some cases the elevated activity seems to stem from induction of the type II isoenzyme (9, 11, 12), although similar up-regulation of both isoforms in activated T-lymphocytes has also been reported (14). These observations suggest that inhibition of IMPDH, or perhaps selective inhibition of individual isoforms, has potential for immunosuppressive or anti-neoplastic therapies. Indeed, inhibition of IMPDH in cultured cells results in decreased guanine nucleotide levels. Ultimately, this leads to the induction of differentiation in neoplastic cells (8) and the suppression of lymphocyte activation (16).Mycophenolic acid (MPA), an uncompetitive inhibitor of IMPDH that was originally identified in certain Penicillium cultures (17), is a potent immunosuppressant, bot...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Conformational Changes and Stabilization of Inosine 5′-Monophosphate Dehydrogenase Associated with Ligand Binding and Inhibition by Mycophenolic Acid

Nimmesgern

Fox

Fleming

et al. 1996

Journal of Biological Chemistry

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“…It has been shown that the free concentration of MPA is variable in renal transplant patients with different renal function. The bioavailabil-ity of MPA is around 94% and the maximum plasma concentration of MPA following an oral dose is reached in around 0.8 h. The average plasma half-life for healthy adults is approximately 16 h (Shaw et al, 1995;Matsuzawa and Nakase, 1984).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of mycophenolic acid in Chinese kidney transplant patients

Huang

Sheng-Tu

et al. 2005

J. Zhejiang Univ. Sci.

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Abstract:To assess the influence of cyclosporin A (CsA) and tacrolimus (FK506) on mycophenolic acid (MPA) and correlation analysis of the pharmacokinetic parameters and patient characteristics, clinical outcome in Chinese kidney transplant recipients, the pharmacokinetics of 1000 mg mycophenolate mofetil (MMF) twice daily was measured by high-performance liquid chromatography (HPLC). PKS (Pharmaceutical Kinetics Software) 1.0.2 software package was used for the calculation of pharmacokinetic parameters. The mean C max , t max , and AUC (0−12) were (21.88±10.52) µg/ml, (1.20±0.95) h, and (52.546±13.215) µg·h/ml, respectively. The level of AUC (0−12) in the FK506 group was significantly higher than that in the CsA group. MPA appeared not to be affected by renal function. MPA AUC (0−12) showed statistically significant difference according to the patient's gender.

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“…Indeed, substances blocking IMPDH activity, such as mycophenolic acid (MPA), act as immunosuppressive drugs and are used to prevent allograft rejection (11)(12)(13)(14)(15)(16)see Ref. 17 for recent reviews).…”

mentioning

confidence: 99%

Transcriptional Regulation of the Yeast GMP Synthesis Pathway by Its End Products

Escobar-Henriques

Daignan‐Fornier

2001

Journal of Biological Chemistry

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AMP and GMP are synthesized from IMP by specific conserved pathways. In yeast, whereas IMP and AMP synthesis are coregulated, we found that the GMP synthesis pathway is specifically regulated. Transcription of the IMD genes, encoding the yeast homologs of IMP dehydrogenase, was repressed by extracellular guanine. Only this first step of GDP synthesis pathway is regulated, since the latter steps, encoded by the GUA1 and GUK1 genes, are guanine-insensitive. Use of mutants affecting GDP metabolism revealed that guanine had to be transformed into GDP to allow repression of the IMD genes. IMD gene transcription was also strongly activated by mycophenolic acid (MPA), a specific inhibitor of IMP dehydrogenase activity. Serial deletions of the IMD2 gene promoter revealed the presence of a negative cis-element, required for guanine regulation. Point mutations in this guanine response element strongly enhanced IMD2 expression, also making it insensitive to guanine and MPA. From these data, we propose that the guanine response element sequence mediates a repression process, which is enhanced by guanine addition, through GDP or a GDP derivative, and abolished in the presence of MPA.Purine nucleotides are involved in many important cellular processes, and therefore a balanced synthesis of AMP and GMP is required. Cells can synthesize purine nucleotides through the de novo pathway, a 10-step pathway that produces IMP, which in turn serves as the common precursor for AMP and GMP nucleotide biosynthesis (Fig. 1). In yeast, the regulation of the ADE genes involved in AMP biosynthesis has been characterized (1, 2). Expression of the ADE genes is repressed by extracellular adenine and activated by the transcription factors Bas1p and Bas2p. However, in Saccharomyces cerevisiae, GMP biosynthesis regulation has not received much attention and is therefore poorly understood. IMP dehydrogenase (IMPDH), 1 catalyzing the first step of de novo guanine nucleotide synthesis, has a key role on growth of many cell types, including lymphocytes and rapidly proliferating cells (see Ref. 3 for a recent review).GMP synthesis and its regulation appear to play a crucial role in cell proliferation, since an increased level of IMPDH activity has been observed in rapidly proliferating cells (4), including human leukemic cell lines (6 -9), solid tumor tissues (10), and B-and T-activated lymphocytes (5). Indeed, substances blocking IMPDH activity, such as mycophenolic acid (MPA), act as immunosuppressive drugs and are used to prevent allograft rejection (11-16; see Ref. 17 for recent reviews). Moreover, it was recently shown that a low level of IMPDH activity is necessary for p53-dependent growth suppression. Indeed, constitutive expression of IMPDH abolishes p53-dependent growth suppression (18), although the exact mechanism is not known.To assess the molecular mechanisms governing guanylic nucleotide synthesis, we have proceeded to study the regulation of GTP synthesis in Saccharomyces cerevisiae. In this yeast, GMP synthetase, GMP kinase, and NDP kin...

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Mycophenolate Mofetil: A Report of the Consensus Panel

Cited by 111 publications

References 0 publications

Conformational Changes and Stabilization of Inosine 5′-Monophosphate Dehydrogenase Associated with Ligand Binding and Inhibition by Mycophenolic Acid

Conformational Changes and Stabilization of Inosine 5′-Monophosphate Dehydrogenase Associated with Ligand Binding and Inhibition by Mycophenolic Acid

Pharmacokinetics of mycophenolic acid in Chinese kidney transplant patients

Transcriptional Regulation of the Yeast GMP Synthesis Pathway by Its End Products

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