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folate polyglutamylation

Background Folates are required in a variety of reactions (known as one-carbon metabolism) in both bacterial and mammalian tissues, where they act as carriers of one-carbon units in various oxidation states. These one-carbon units are utilized in the biosynthesis of various cellular components, including glycine, methionine, thymidylate, pantothenate and purine nucleotides. Folates are essential for DNA synthesis, repair and methylation. Humans cannot synthesize folates de novo, and require vitamin B9 (folic acid) as a regular dietary supplement to meet folate demands. The enzyme : CPLX66-351 reduces : DIHYDROFOLATE, a derivative of vitamin B9, to : THF. : THF "Tetrahydrofolate" can be converted to several other folate molecules . More commonly, folate molecules are further modified in cells by successive additions of glutamate residues, forming folate polyglutamates. The glutamates are often added bygamma-carboxy-linked polyglutamylation via an amide linkage to the gamma-carboxylate group of the folate or folate derivative. Since these isopeptide bonds are not normal amide bonds, they are not hydrolyzed by peptidases or proteases that are specific for alpha-carboxyl-linked peptide bonds. The addition of glutamyl residues probably occurs to tetrahydrofolate and its derivatives. The glutamylation of folate residues has several goals, it prevents the efflux of folates out of the cell, increases the binding of folate cofactors to the enzymes of folate interconversion and biosynthesis. In mammals, it also allows the accumulation of folates in the mitochondria, where it is required for glycine synthesis . About this Pathway The bifunctional enzyme : HS06237-MONOMER catalyzes the conversion of folates to polyglutamates. It is a Mg2+ATP-dependent enzyme ubiquitiously expressed. The enzyme forms a complex with Mg2+ATP, a folate derivative and glutamate, in an ordered manner whereby the three substrates are added sequentially . Folylpolyglutamate synthetase can accept several different folate derivatives as substrates. It seems that the preferred substrate for the addition of a second glutamate residue is : 10-FORMYL-THF, while the preferred substrate for the addition of a third glutamate residue is the glutamated form of : METHYLENE-THF. Folylpolyglutamates are generally better substrates for folate-dependent enzymes than their monoglutamyl counterparts. Km values decrease with increasing oligo-gamma-glutamyl chain length . The vitamin B12-dependent : HS04076-MONOMER has a requirement for the polyglutamate cofactor . Many folate enzymes are multifunctional and channel one-carbon units between reactions without achieving equilibrium with the cell medium. Therefore, the conjugated oligo-gamma-glutamyl chain can potentially regulate the reaction rates, and allows channeling of the substrate between enzymes in a way which controls biosynthetic pathways .

from BIOCYC source record: HUMAN_PWY-2161
Type: pathway
Taxonomic scope
organism-specific biosystem
Homo sapiens

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