English Journal

Biochemical characterization of recombinant dihydroorotate dehydrogenase from the opportunistic pathogenic yeast Candida albicans.

Zameitat E1, Gojković Z, Knecht W, Piskur J, Löffler M.Author information 1Institute for Physiological Chemistry, Philipps-University, Marburg, Germany. zameitat@gmx.deAbstractCandida albicans is the most prevalent yeast pathogen in humans, and recently it has become increasingly resistant to the current antifungal agents. In this study we investigated C. albicans dihydroorotate dehydrogenase (DHODH, EC 1.3.99.11), which catalyzes the fourth step of de novo pyrimidine synthesis, as a new target for controlling infection. We propose that the enzyme is a member of the DHODH family 2, which comprises mitochondrially bound enzymes, with quinone as the direct electron acceptor and oxygen as the final electron acceptor. Full-length DHODH and N-terminally truncated DHODH, which lacks the targeting sequence and the transmembrane domain, were subcloned from C. albicans, recombinantly expressed in Escherichia coli, purified, and characterized for their kinetics and substrate specificity. An inhibitor screening with 28 selected compounds was performed. Only the dianisidine derivative, redoxal, and the biphenyl quinoline-carboxylic acid derivative, brequinar sodium, which are known to be potent inhibitors of mammalian DHODH, markedly reduced C. albicans DHODH activity. This study provides a background for the development of antipyrimidines with high efficacy for decreasing in situ pyrimidine nucleotide pools in C. albicans.
The FEBS journal.FEBS J.2006 Jul;273(14):3183-91. Epub 2006 Jun 15.
Candida albicans is the most prevalent yeast pathogen in humans, and recently it has become increasingly resistant to the current antifungal agents. In this study we investigated C. albicans dihydroorotate dehydrogenase (DHODH, EC 1.3.99.11), which catalyzes the fourth step of de novo pyrimidine syn
PMID 16774642

Antimetabolite incorporation into DNA: structural and thermodynamic basis for anticancer activity.

Gmeiner WH.Author information Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. bgmeiner@wfubmc.eduAbstractAntimetabolites are a class of effective anticancer drugs that structurally resemble naturally occurring biochemicals and interfere in essential biochemical processes. In this review, the recent literature describing investigations of the structural and thermodynamic basis for the anticancer activity of three antipyrimidines [1-beta-D-arabinofuranosyl cytidine (AraC). 2',2'-difluoro deoxycytidine (dFdC), and 5-fluoro-2'-deoxyuridine (FdUrd)] is summarized. Our laboratory, and others, have shown that misincorporation of any of these three antipyrimidines into DNA perturbs the structure and decreases the stability of duplex DNA. These data are useful for rationalizing the effects of antipyrimidine misincorporation on the activities of proteins required for DNA replication and repair such as DNA topoisomerase 1 and DNA polymerases. The studies completed to date and summarized in this review demonstrate the utility of investigations into the structure-function relationships between antipyrimidine-substituted DNA complexed with DNA-modifying proteins for the purpose of understanding the basis for effective antipyrimidine cancer chemotherapy and the future design of novel anticancer drugs.
Biopolymers.Biopolymers.2002 Nov 5;65(3):180-9.
Antimetabolites are a class of effective anticancer drugs that structurally resemble naturally occurring biochemicals and interfere in essential biochemical processes. In this review, the recent literature describing investigations of the structural and thermodynamic basis for the anticancer activit
PMID 12228923

New treatments for rheumatoid arthritis. Available and upcoming slow-acting antirheumatic drugs.

Fye KH.Author information Division of Rheumatology, UCSF 94143-0326, USA.AbstractNo single therapeutic agent has been found to be universally effective for rheumatoid arthritis, so regimens using combinations of drugs have become the rule. Recently, several new agents with unique mechanisms of action have been introduced and found to produce various degrees of clinical benefit. Among these agents are folate and purine antagonists, alkylating agents, and antipyrimidines. Chimeric (mouse/ human) monoclonal antibody to tumor necrosis factor-alpha and human recombinant interleukin-1 receptor antagonist await approval for general use but have undergone considerable study.
Postgraduate medicine.Postgrad Med.1999 Oct 1;106(4):82-5, 88-90, 92.
No single therapeutic agent has been found to be universally effective for rheumatoid arthritis, so regimens using combinations of drugs have become the rule. Recently, several new agents with unique mechanisms of action have been introduced and found to produce various degrees of clinical benefit.
PMID 10533510

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