Folate biosynthesis inhibition

Similar equations have been derived for bacterial systems, comparing the folate biosynthesis inhibition Iso of a series of 4 -substituted 4-aminodiphenyl sulfones (45) in a cell-free system with Escherichia coli and Mycobacterium smegmatis (eq. 186) cell culture inhibition, MIC (log k is a HPLC capacity factor, closely related to lipophilicity, expressed by7t n = 15 r = 0.994) [596]. 

Very little interest in the subject was shown until the late 1960s when Roth (69JMC227) undertook studies in chemotherapy based on inhibition of folate biosynthesis and function by certain 2,4-diaminothieno[2,3-[Pg.194]

Folate analogues, such as methotrexate (Figure 27-3), are folate antagonists. They block production of FH2 and FH4 by dihydrofolate reductase and lead to diminished purine biosynthesis (inhibition of reactions 3 and 9 in Figure 27-8). Methotrexate also affects metabolism of amino acids and pyrimidine (inhibition of thymidylate synthesis) and inhibits DNA, RNA, and protein synthesis. It is effective in the treatment of breast cancer, cancer of the head and neck, choriocarcinoma, osteogenic sarcoma, and acute forms of leukemia. High doses of methotrexate can be tolerated provided that the patient also receives folinic... 

Several reactions of IMP biosynthesis require folate derivatives and glutamine. Consequently, antifolate drugs and glutamine analogs inhibit purine biosynthesis. 

Inhibit Enzymes Many drugs are competitive inhibitors of key enzymes in pathways. The statin drugs (lovastatin, simvastatin), used to control blood cholesterol levels, competitively inhibit 3-hvdroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in cholesterol biosynthesis. Methotrexate, an antineoplastic drug, competitively inhibits dihydrofolate reductase, depriving the cell of active folate needed for purine and deoxythymidine synthesis, thus interfering with DNA replication during S phase. 

These are pyrimidine derivatives and are effective because of differences in susceptibility between the enzymes in humans and in the infective organism. Anticancer agents based on folic acid, e.g. methotrexate, inhibit dihydrofolate reductase, but they are less selective than the antimicrobial agents and rely on a stronger binding to the enzyme than the natural substrate has. They also block pyrimidine biosynthesis. Methotrexate treatment is potentially lethal to the patient, and is usually followed by rescue with folinic acid (A -formyl-tetrahydrofolic acid) to counteract the folate-antagonist action. The rationale is that folinic acid rescues normal cells more effectively than it does tumour cells. 

Many drugs interact with folate to affect its absorption, antagonize its biochemical activity, or increase its loss from the body. These drugs include ethanol, phenytoin, and oral contraceptives. Salicylates can compete with foUc acid for plasma protein binding. Methotrexate, a cytotoxic agent, is a folate antagonist that inhibits the biosynthesis of this coenzyme. 

Fumonisin inhibition of de novo sphingolipid biosynthesis (Merrill et ah, 2001 Riley et ah, 1996), resulting in depletion of complex glyco-sphingolipids, disruption of lipid rafts, and compromised folate transport via Folrl, which may have significant implications with respect to developmental anomalies such as NTDs (Hansen et ah, 2003 Piedrahita... 

Folate in the human organism is converted to tetrahydrofolate (THF or FH4) by a reductive process. The reduction reaction is a stepwise one folate to dihydrofolate, then to THF. A single enzyme, dihydrofolate reductase, catalyzes both steps. The reaction is inhibited by folate analogues and the antitumor agents methotrexate and aminopterin (Figure 6.3). Because THF is required for DNA biosynthesis (Chapter 10) and tumors have a very high level of DNA biosynthetic activity, even modest decreases in THF availability will inhibit tumor growth. 

Tetrahydrofolic acid (THF) is a coenzyme in the synthesis of purine bases and thymidine. These are constituents of DNA and RNA and are required for cell growth and replication. Lack of THF leads to inhibition of cell proliferation. Formation of THF from dihydrofolate (DHF) is catalyzed by the enzyme dihydrofolate reductase. DHF is made from folic acid, a vitamin that cannot be synthesized in the body but must be taken up from exogenous sources. Most bacteria do not have a requirement for folate, because they are capable of synthesizing it-more precisely DHF-ffom precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim. 

Deficiency of folate or vitamin Bn can cause hematological changes similar to hereditary orotic aciduria. Folate is directly involved in thymidylic acid synthesis and indirectly involved in vitamin Bn synthesis. Orotic aciduria without the characteristic hematological abnormalities occurs in disorders of the urea cycle that lead to accumulation of carbamoyl phosphate in mitochondria (e.g., ornithine transcarbamoylase deficiency see Chapter 17). The carbamoyl phosphate exits from the mitochondria and augments cytosolic pyrimidine biosynthesis. Treatment with allopurinol or 6-azauridine also produces orotic aciduria as a result of inhibition of orotidine-5 phosphate decarboxylase by their metabolic products. 

Dihydrofolate reductase (DHFR, EC 1.5.1.3) is an essential enzyme required for normal folate metabolism in prokaryotes and eukaryotes. Its role is to maintain necessary levels of tetrahydrofolate to support the biosynthesis of purines, pyrimidines and amino acids. Many compounds of pharmacological value, notably methotrexate and trimethoprim, vork by inhibition of DHFR. Their clinical importance justified the study of DHFR in the rapidly evolving field of enzymology. Today, there is a vast amount of published literature (ca. 1000 original research articles) on the broad subject of dihydrofolate reductase contributed by scientists from diverse disciplines. We have selected kinetic, structural, and computational studies that have advanced our understanding of the DHFR catalytic mechanism with special emphasis on the role of the enzyme-substrate complexes and protein motion in the catalytic efficiency achieved by this enzyme. 

Subsequent work established that the sulfonamides inhibit the biosynthesis of folate at the level of dihydropteroate synthase (Figure 2, g). More specifically, the compounds can be used as substrates of the enzyme, but the resulting conjugates cannot serve as substrates for the subsequent enzymatic steps resulting in the addition of an oligoglutamate tail the products generated by dihydropteroate synthase with sulfa drugs as substrates can therefore not serve the THF requirement of the parasite. 

Methotrexate, a folate antagonist, interferes vAth nucleic acid biosynthesis. Would you expect it to inhibit purine or pyrimidine biosynthesis or both processes Explain. 

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