Editing Folate (section)

== Absorption, metabolism and excretion ==
Folate in food is roughly one-third in the form of monoglutamate and two-thirds polyglutamate; the latter is hydrolyzed to monoglutamate via a reaction mediated by [[folate conjugase]] at the brush border of enterocytes in the proximal small intestine.<ref name="Alpers2016">{{cite journal |vauthors=Alpers DH |title=Absorption and blood/cellular transport of folate and cobalamin: Pharmacokinetic and physiological considerations |journal=Biochimie |volume=126 |issue= |pages=52–6 |date=July 2016 |pmid=26586110 |pmc=4867132 |doi=10.1016/j.biochi.2015.11.006 |url=}}</ref> Subsequently, intestinal absorption is primarily accomplished by the action of the [[proton-coupled folate transporter]] (PCFT) protein coded for by the ''SLC46A1'' gene. This functions best at [[pH]] 5.5, which corresponds to the acidic status of the proximal small intestine. PCFT binds to both reduced folates and folic acid. A secondary folate transporter is the [[reduced folate carrier]] (RFC), coded for by the ''SLC19A1'' gene. It operates optimally at pH 7.4 in the [[ileum]] portion of the small intestine. It has a low affinity for folic acid. Production of the receptor proteins is increased in times of folate deficiency.<ref name="Said2011"/> In addition to a role in intestinal absorption, RFC is expressed in virtually all tissues and is the major route of delivery of folate to cells within the systemic circulation under physiological conditions. When pharmacological amounts of folate are taken as a dietary supplement, absorption also takes place by a passive diffusion-like process.<ref name=PKIN2020Folate /><ref name="Visentin2014">{{cite journal |vauthors=Visentin M, Diop-Bove N, Zhao R, Goldman ID |title=The intestinal absorption of folates |journal=Annu Rev Physiol |volume=76 |issue= |pages=251–74 |date=2014 |pmid=24512081 |pmc=3982215 |doi=10.1146/annurev-physiol-020911-153251 |url=}}</ref> In addition, bacteria in the distal portion of the small intestine and in the large intestine synthesize modest amounts of folate, and there are RFC receptors in the large intestine, so this in situ source may contribute to toward the cellular nutrition and health of the local colonocytes.<ref name="Said2011">{{cite journal |vauthors=Said HM |title=Intestinal absorption of water-soluble vitamins in health and disease |journal=Biochem J |volume=437 |issue=3 |pages=357–72 |date=August 2011 |pmid=21749321 |pmc=4049159 |doi=10.1042/BJ20110326 |url=}}</ref><ref name="Visentin2014"/>

The biological activity of folate in the body depends upon [[dihydrofolate reductase]] action in the liver which converts folate into [[tetrahydrofolate]] (THF). This action is rate-limiting in humans leading to elevated blood concentrations of unmetabolized folic acid when consumption from dietary supplements and fortified foods nears or exceeds the U.S. [[Dietary Reference Intake#Parameters|Tolerable Upper Intake Level]] of 1,000&nbsp;μg per day.<ref name=PKIN2020Folate /><ref name = "Bailey">{{cite journal | vauthors = Bailey SW, Ayling JE | title = The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 36 | pages = 15424–9 | date = September 2009 | pmid = 19706381 | pmc = 2730961 | doi = 10.1073/pnas.0902072106 | bibcode = 2009PNAS..10615424B| doi-access = free }}</ref>

The total human body content of folate is estimated to be approximately 15–30 milligrams, with approximately half in the liver.<ref name=PKIN2020Folate /> Excretion is via urine and feces. Under normal dietary intake, urinary excretion is mainly as folate cleavage products, but if a dietary supplement is being consumed then there will be intact folate in the urine. The liver produces folate-containing bile, which if not all absorbed in the small intestine, contributes to fecal folate, intact and as cleavage products, which under normal dietary intake has been estimated to be similar in amount to urinary excretion. Fecal content includes what is synthesized by intestinal microflora.<ref name=PKIN2020Folate />

=== Biosynthesis ===
Animals, including humans, cannot synthesize (produce) folate and therefore must obtain folate from their diet. All plants and fungi and certain protozoa, bacteria, and [[archaea]] can synthesize folate [[de novo synthesis|de novo]] through variations on the same [[biosynthesis|biosynthetic]] pathway.<ref name="Rossi_2011">{{cite journal | vauthors = Rossi M, Amaretti A, Raimondi S | title = Folate production by probiotic bacteria | journal = Nutrients | volume = 3 | issue = 1 | pages = 118–34 | date = January 2011 | pmid = 22254078 | pmc = 3257725 | doi = 10.3390/nu3010118 | doi-access = free }}</ref> The folate molecule is synthesized from pterin pyrophosphate, [[para-aminobenzoic acid|''para''-aminobenzoic acid]] (PABA), and [[glutamate]] through the action of [[dihydropteroate synthase]] and [[dihydrofolate synthase]]. Pterin is in turn derived in a series of enzymatically catalyzed steps from [[guanosine triphosphate]] (GTP), while PABA is a product of the [[shikimate pathway]].<ref name="Rossi_2011" />

=== 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>