Mycophenolic Acid an Antibiotic From Penicillium Brevicompactum Dierckx

Florey, H. W.; Jennings, M. A.; Gilliver, K.; Sanders, A. G.

doi:10.1016/s0140-6736(46)90242-5

Cited by 104 publications

(53 citation statements)

References 5 publications

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“…IMPDH inhibitors are used clinically in antiviral (ribavirin) and immunosuppressive therapies (mycophenolate mofetil and mizoribine) (2)(3)(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)(8)(9).…”

mentioning

confidence: 99%

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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confidence: 99%

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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“…Mycophenolate mofetil (MMF) was initially introduced in 1946 as an antibiotic from Penicillium brevicompactum (Florey et al 1946) and was first used as an immunosuppressant in the 1970s to treat psoriasis (Spatz et al 1978). Two decades later it was utilized in solid organ transplant recipients as an alternative to other immunosuppressive agents associated with undesirable side effects due to their non-selective antiproliferative mechanism (Allison and Eugui 1993).…”

Section: Mycophenolate Mofetilmentioning

confidence: 99%

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

Narayanan

Kuppermann

2016

Handbook of Experimental Pharmacology

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“…in 1896. [1] Its antibacterial and antifungal properties were detected in 1946 [2,3] and its antiviral and antitumour activities in 1968. [4] Mycophenolate mofetil (CellCept ¾ , Roche Inc., Basel, Switzerland) was developed in the 1960×s as an antibiotic, antineoplastic and antipsoriatic drug, and was later also used for immunosuppression after solid tumour transplantations.…”

Section: Introductionmentioning

confidence: 99%

Preparative Enzymatic Synthesis of the Acylglucuronide of Mycophenolic Acid

Kittelmann¹,

Rheinegger²,

Espigat³

et al. 2003

Adv Synth Catal

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The acylglucuronide (3) of mycophenolic acid (1) was enzymatically synthesised on a preparative scale (450 mg substrate) under optimised reaction conditions with 51% conversion. By screening 9 liver homogenates from 8 vertebrate species, it was shown that only with liver homogenate from horse as the catalyst were the acyl-(3) and the O-glucuronide (2) were formed in a ca. 1 : 1 ratio. With homogenates from other sources, the O-glucuronide (2) was produced in high excess. By optimising the concentration of the co-substrate UDP-glucuronic acid and the reaction temperature, the conversion to the acylglucuronide (3) was increased from initially 34 to 55% and the ratio of acyl-(3) to O-glucuronide (2) from 1.5 : 1 to 3.9 : 1. The reaction was also performed continuously in an enzyme membrane reactor, however, with lower conversion yield and therefore, higher specific UDP-glucuronic acid consumption.

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Mycophenolic Acid an Antibiotic From Penicillium Brevicompactum Dierckx

Cited by 104 publications

References 5 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

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

Preparative Enzymatic Synthesis of the Acylglucuronide of Mycophenolic Acid

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