) and the amino acid glutamate. The biologically active derivatives are 5,6,7,8-tetrahydrofolates (THF) with 1C units at the N5, N10 positions or both. Their interconversion(s) assures the continuous provision of these important derivatives. The various aspects of folate uptake, processing and interconversion constitute the metabolic pathway of the folate cycle and are presented here. The important folate mediated 1C transfer reactions and the pathways and processes they support constitute the folate mediated one-carbon metabolic pathway and are presented in a separate diagram. Together they are part of the folate metabolic pathway. Dietary folates circulate as polyglutamates, also the forms that are better retained in the cell and are better substrates for the folate dependent enzymes. The uptake and transport of folates however, require the monoglutamic form. Hydrolysis of polyglutamates outside and inside the cell and addition of glutamates to the monoglutamate form are important for maintaining an adequate pool of biological active THFs and the balance between their influx and efflux. The intestinal apical brush border membrane anchored Folh1 hydrolyzes the polyGluTHFs which are then absorbed in the duodenum and jejunum by the Slc46a1 proton-coupled transporter. Circulating folates are transported into the cell by the folate receptors 1 and 2 and by Slc19a1 reduced folate carrier. MonoGluTHFs are taken up in the mitochondria by the Slc25a32 transporter. If FA is the folate source, it must first be reduced to dyhdrofolate (DHF) and then to THF by Dhfr. In the cell, addition of up to nine glutamate residues is mediated by Fpgs while their removal is mediated by the lysosomal enzyme Ggh. Segregation of the two processes allows cells to control the occurrence of the two reactions. The ratio of the two enzymatic activities is also important for the processing and availability of various antifolate drugs such as methotrexate (MTX). 1C units are derived primarily from serine, but also from glycine, dimethylglycine (DMG) and sarcosine. Mitochondria and the cytoplasm represent the major pools of folates and in the two compartments the interconversion of THF derivatives is largely carried out by separate enzymes. Serine is a major source of 1C; its transfer to THF generates 5,10-methyleneTHF and glycine in the reversible reaction catalyzed by the pyridoxal-5'-phosphate (PLP/vitamin B6) dependent Shmt1 and Shmt2 enzymes in the cytoplasm and mitochondria, respectively. 5,10-methyleneTHF can be oxidized to 10-formylTHF (FTHF) and formate or reduced to 5-methylTHF. 5,10-methyleneTHF, FTFH and 5-methylTHF are the 1C donors for the three important 1C transfer reactions and are highlighted along with the THF-co-factor with a different color. Mitochondria generate formate from THF. Shmt2 converts THF and serine (mSer) to 5,10-methyleneTHF. The glycine cleavage system (GCS) - a multienzyme complex of four subunits, uses glycine (mGly) to generate 5,10-methyleneTHF. Of the four GCS subunits, three are unique and one is shared with other mitochondrial complexes. Dimethylglycine (DMG) and sarcosine, derived from choline oxidation, are the other sources of 5,10-methyleneTHF generation in reactions catalyzed by Dmgdh and Sardh, respectively. The four enzymes/complex are associated with the inner mitochondrial membrane. 5,10-methyleneTHF is then sequentially processed to 5,10-methenylTHF and to FTFH by two bifunctional enzymes Mthfd and Mthfd2l; FTFH is then used to generate formate in the reaction catalyzed by Mthfd1l. Formate is transported to the cytoplasm where is condensed with THF to yield FTHF in the ATP-dependent reaction catalyzed by the trifunctional Mthfd1 enzyme. In the cytoplasm, 5,10-methyleneTHF generated by Shmt1 is the substrate for Mthfr, the FAD (flavin adenine dinucleotide), NADPH dependent enzyme which irreversibly converts it to 5-methylTHF. 5-methylTHF is the 1C donor for the cobalamin dependent Mtr mediated re-methylation of Hcy to Met in the homocysteine and methionine cycle metabolic pathways. Interconversion of 5,10-methyleneTHF and 5,10 methenylTHF (dehydrogenase reaction) and of 5,10-methenyl and FTFH (cyclohydrolase reaction) and the reaction of formate with THF generating FTFH (synthetase reaction are carried out by the trifunctional enzyme Mthfd1. The mammalian enzyme contains the synthetase activity on the C-terminal domain; the dehydrogenase and cyclohydrolase activities are on the N-terminal domain. FTFH can also be irreversibly converted to THF and CO2 in the NADP-dependent reaction catalyzed by Aldh1l1, an abundant enzyme in the liver. The Aldh1l1 mediated reaction regulates cellular concentration of FTHF. The pathways of methionine, homocysteine and folate metabolism are intimately interconnected. Defects in enzymes within these pathways have been associated with several disorders and conditions. To see the ontology report for Gviewer, annotations and download, click here ...(less)