Mycophenolic Acid:  A One Hundred Year Odyssey from Antibiotic to Immunosuppressant

Bentley, Ronald

doi:10.1021/cr990097b

Cited by 272 publications

(210 citation statements)

References 178 publications

(420 reference statements)

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“…7,33,34 A specific inhibitor of IMPDH enzymes, MPA has been used as an immunosuppressant during organ transplant. [35][36][37] A better bioavailable form of MPA is its prodrug MMF (over 200% improvement in bioavailability), 38 which has also been proposed as anti-cancer therapy. 39,40 Therefore, for the purpose of comparison, we evaluated angustmycin A head-to-head with MMF.…”

Section: Gmps Controls Melanoma Cell Invasionmentioning

confidence: 99%

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

et al. 2015

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Malignant melanoma possesses one of the highest metastatic potentials among human cancers. Acquisition of invasive phenotypes is a prerequisite for melanoma metastases. Elucidation of the molecular mechanisms underlying melanoma invasion will greatly enhance the design of novel agents for melanoma therapeutic intervention. Here, we report that guanosine monophosphate synthase (GMPS), an enzyme required for the de novo biosynthesis of GMP, has a major role in invasion and tumorigenicity of cells derived from either BRAF V600E or NRAS Q61R human metastatic melanomas. Moreover, GMPS levels are increased in metastatic human melanoma specimens compared with primary melanomas arguing that GMPS is an attractive candidate for anti-melanoma therapy. Accordingly, for the first time we demonstrate that angustmycin A, a nucleoside-analog inhibitor of GMPS produced by Streptomyces hygroscopius efficiently suppresses melanoma cell invasion in vitro and tumorigenicity in immunocompromised mice. Our data identify GMPS as a powerful driver of melanoma cell invasion and warrant further investigation of angustmycin A as a novel anti-melanoma agent.

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Section: Gmps Controls Melanoma Cell Invasionmentioning

confidence: 99%

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

et al. 2015

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“…PR toxin inhibits protein and RNA synthesis (21,22), is mutagenic in the Salmonella typhimurium assay (23), and is carcinogenic in rats (24). Mycophenolic acid is antibacterial and immunosuppressive in higher animals (25). In a feeding experiment with sheep, no roquefortine toxicity was revealed (26); however, others have shown it to be antibacterial (27), and in a more recent study, it (and mycophenolic acid) has been shown to be highly toxic when inhaled by mice (28).…”

Section: Introductionmentioning

confidence: 99%

Mycotoxins and Other Secondary Metabolites Produced in Vitro byPenicillium paneumFrisvad andPenicillium roquefortiThom Isolated from Baled Grass Silage in Ireland

O’Brien

Nielsen

O’Kiely

et al. 2006

J. Agric. Food Chem.

110

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Secondary metabolites produced by Penicillium paneum and Penicillium roqueforti from baled grass silage were analyzed. A total of 157 isolates were investigated, comprising 78 P. paneum and 79 P. roqueforti isolates randomly selected from more than 900 colonies cultured from bales. The findings mostly agreed with the literature, although some metabolites were not consistently produced by either fungus. Roquefortine C, marcfortine A, and andrastin A were consistently produced, whereas PR toxin and patulin were not. Five silage samples were screened for fungal metabolites, with two visually moldy samples containing up to 20 mg/kg of roquefortine C, mycophenolic acid, and andrastin A along with minor quantities (0.1-5 mg/kg) of roquefortines A, B, and D, festuclavine, marcfortine A, and agroclavine. Three visually nonmoldy samples contained low amounts of mycophenolic acid and andrastin A. The ability of both molds to produce a diverse range of secondary metabolites in vitro and in silage should be a concern to livestock producers.

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“…Among the topmost hits were three cytochrome P450 enzymes, all known to catalyze hydroxylations. These hits included the Rattus norvegicus CYP24A1 catalyzing hydroxylation of 25-hydroxyvitamin D 3 (1), the human CYP2D6 catalyzing hydroxylation of debrisoquine (24), and P450 BM3 from Bacillus megaterium that catalyzes hydroxylation of several long-chain fatty acids (7). Multiple sequence alignments of MpaD with the three aforementioned CYP strains, as well as Talaromyces stipitatus TSTA_060710 and Phaeosphaeria nodorum SNOG_06679, revealed that the P450 heme signature motif and the EXXR motif of the P450 heme thiolate enzymes are conserved in MpaD (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…MPA has also been associated with antiviral, antifungal, antibacterial, and antitumor activities (11). Consequently, MPA biosynthesis has received considerable research interest, and a biosynthetic route has been established through chemical labeling and culture feeding studies (3). MPA is a meroterpenoid proposed to be derived from a nonreduced tetraketide moiety through a five-step process involving oxidation, lactonization, and condensation with a farnesyl residue, followed by oxidative cleavage of the terpene part and a final methylation step (Fig.…”

mentioning

confidence: 99%

Involvement of a Natural Fusion of a Cytochrome P450 and a Hydrolase in Mycophenolic Acid Biosynthesis

Hansen

Mnich

Nielsen

et al. 2012

Appl Environ Microbiol

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Mycophenolic acid (MPA) is a fungal secondary metabolite and the active component in several immunosuppressive pharmaceuticals. The gene cluster coding for the MPA biosynthetic pathway has recently been discovered in Penicillium brevicompactum, demonstrating that the first step is catalyzed by MpaC, a polyketide synthase producing 5-methylorsellinic acid (5-MOA). However, the biochemical role of the enzymes encoded by the remaining genes in the MPA gene cluster is still unknown. Based on bioinformatic analysis of the MPA gene cluster, we hypothesized that the step following 5-MOA production in the pathway is carried out by a natural fusion enzyme MpaDE, consisting of a cytochrome P450 (MpaD) in the N-terminal region and a hydrolase (MpaE) in the C-terminal region. We verified that the fusion gene is indeed expressed in P. brevicompactum by obtaining full-length sequence of the mpaDE cDNA prepared from the extracted RNA. Heterologous coexpression of mpaC and the fusion gene mpaDE in the MPA-nonproducer Aspergillus nidulans resulted in the production of 5,7-dihydroxy-4-methylphthalide (DHMP), the second intermediate in MPA biosynthesis. Analysis of the strain coexpressing mpaC and the mpaD part of mpaDE shows that the P450 catalyzes hydroxylation of 5-MOA to 4,6-dihydroxy-2-(hydroxymethyl)-3-methylbenzoic acid (DHMB). DHMB is then converted to DHMP, and our results suggest that the hydrolase domain aids this second step by acting as a lactone synthase that catalyzes the ring closure. Overall, the chimeric enzyme MpaDE provides insight into the genetic organization of the MPA biosynthesis pathway.

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Mycophenolic Acid: A One Hundred Year Odyssey from Antibiotic to Immunosuppressant

Cited by 272 publications

References 178 publications

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

Mycotoxins and Other Secondary Metabolites Produced in Vitro byPenicillium paneumFrisvad andPenicillium roquefortiThom Isolated from Baled Grass Silage in Ireland

Involvement of a Natural Fusion of a Cytochrome P450 and a Hydrolase in Mycophenolic Acid Biosynthesis

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