Editing Folate (section)

=== Bioactivation ===
[[File:Folic Acid Biotransformations.svg|thumb|400px|class=skin-invert-image|Biotransformation of folic acid into [[folinic acid]]s where R = ''para''-aminobenzoate-glutamate<ref name = "Carmen_2008" />]]

All of the biological functions of folic acid are performed by [[tetrahydrofolate|THF]] and its [[methylated]] derivatives. Hence folic acid must first be [[redox|reduced]] to THF. This four electron reduction proceeds in two chemical steps both catalyzed by the same enzyme, [[dihydrofolate reductase]].<ref name = "Carmen_2008">{{cite book | vauthors = Carmen AJ, Carlos M | title = Medicinal Chemistry of Anticancer Drugs | date = 2008 | chapter = Chapter 2 – Antimetabolites | pages = 9–52 | isbn = 978-0-444-52824-7 | doi = 10.1016/B978-0-444-52824-7.00002-0 | quote = Figure 2.27: Biotransformation of folic acid into folinic acids }}</ref> Folic acid is first reduced to [[dihydrofolate]] and then to tetrahydrofolate. Each step consumes one molecule of [[NADPH]] ([[biosynthesis|biosynthetically]] derived from [[Niacin (nutrient)|vitamin B<sub>3</sub>]]) and produces one molecule of [[NADP]].<ref name=PKIN2020Folate /><ref>{{cite web | url = http://us.expasy.org/enzyme/1.5.1.3 | title = EC 1.5.1.3 | publisher = Us.expasy.org | access-date = 9 September 2012 | url-status = live | archive-url = https://web.archive.org/web/20110613191819/http://us.expasy.org/enzyme/1.5.1.3 | archive-date = 13 June 2011}}</ref> Mechanistically, hydride is transferred from NADPH to the C6 position of the pteridine ring.<ref>{{cite journal | vauthors = Benkovic SJ, Hammes-Schiffer S | s2cid = 7899320 | title = A perspective on enzyme catalysis | journal = Science | volume = 301 | issue = 5637 | pages = 1196–202 | date = August 2003 | pmid = 12947189 | doi = 10.1126/science.1085515 | bibcode = 2003Sci...301.1196B}}</ref>

A one-carbon (1C) methyl group is added to tetrahydrofolate through the action of [[serine hydroxymethyltransferase]] (SHMT) to yield [[5,10-methylenetetrahydrofolate]] (5,10-CH<sub>2</sub>-THF). This reaction also consumes [[serine]] and [[pyridoxal phosphate]] (PLP; vitamin B<sub>6</sub>) and produces [[glycine]] and [[pyridoxal]].<ref name = "Carmen_2008" /> A second enzyme, [[methylenetetrahydrofolate dehydrogenase (NADP+)|methylenetetrahydrofolate dehydrogenase]] ([[MTHFD2]])<ref name="Christensen_2008">{{cite journal | vauthors = Christensen KE, Mackenzie RE | title = Mitochondrial methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetases | journal = Vitamins and Hormones | volume = 79 | pages = 393–410 | date = 2008 | pmid = 18804703 | doi = 10.1016/S0083-6729(08)00414-7 }}</ref> oxidizes 5,10-methylenetetrahydrofolate to an [[iminium]] cation which in turn is [[hydrolyzed]] to produce [[5-formyltetrahydrofolate|5-formyl-THF]] and [[10-formyltetrahydrofolate|10-formyl-THF]].<ref name = "Carmen_2008" /> This series of reactions using the [[alpha and beta carbon|β-carbon]] atom of serine as the carbon source provide the largest part of the one-carbon units available to the cell.<ref name = Stover1990>{{cite journal | vauthors = Stover P, Schirch V | title = Serine hydroxymethyltransferase catalyzes the hydrolysis of 5,10-methenyltetrahydrofolate to 5-formyltetrahydrofolate | journal = The Journal of Biological Chemistry | volume = 265 | issue = 24 | pages = 14227–33 | date = August 1990 | doi = 10.1016/S0021-9258(18)77290-6 | pmid = 2201683 | doi-access = free }}</ref>

Alternative carbon sources include [[formate]] which by the catalytic action of [[formate–tetrahydrofolate ligase]] adds a 1C unit to THF to yield 10-formyl-THF. Glycine, [[histidine]], and [[sarcosine]] can also directly contribute to the THF-bound 1C pool.<ref name="Ducker_2017">{{cite journal | vauthors = Ducker GS, Rabinowitz JD | title = One-Carbon Metabolism in Health and Disease | journal = Cell Metabolism | volume = 25 | issue = 1 | pages = 27–42 | date = January 2017 | pmid = 27641100 | pmc = 5353360 | doi = 10.1016/j.cmet.2016.08.009 }}</ref>