Editing Choline (section)

== Metabolism ==
=== Biosynthesis ===
[[File:Choline biosynthesis.svg|thumb|450px|class=skin-invert-image|[[Biosynthesis]] of choline in plants]]

In plants, the first step in [[de novo synthesis|''de novo'' biosynthesis]] of choline is the [[decarboxylation]] of [[serine]] into [[ethanolamine]], which is catalyzed by a [[decarboxylase|serine decarboxylase]].<ref name="pmid11461929">{{cite journal | vauthors = Rontein D, Nishida I, Tashiro G, Yoshioka K, Wu WI, Voelker DR, Basset G, Hanson AD | title = Plants synthesize ethanolamine by direct decarboxylation of serine using a pyridoxal phosphate enzyme | journal = The Journal of Biological Chemistry | volume = 276 | issue = 38 | pages = 35523–9 | date = September 2001 | pmid = 11461929 | doi = 10.1074/jbc.M106038200 | doi-access = free }}</ref> The synthesis of choline from ethanolamine may take place in three parallel pathways, where three consecutive ''N''-methylation steps catalyzed by a [[methyl transferase]] are carried out on either the free-base,<ref name="pmid16653153">{{cite journal | vauthors = Prud'homme MP, Moore TS | title = Phosphatidylcholine synthesis in castor bean endosperm : free bases as intermediates | journal = Plant Physiology | volume = 100 | issue = 3 | pages = 1527–35 | date = November 1992 | pmid = 16653153 | pmc = 1075815 | doi = 10.1104/pp.100.3.1527 }}</ref> phospho-bases,<ref name="pmid10799484">{{cite journal | vauthors = Nuccio ML, Ziemak MJ, Henry SA, Weretilnyk EA, Hanson AD | title = cDNA cloning of phosphoethanolamine ''N''-methyltransferase from spinach by complementation in ''Schizosaccharomyces pombe'' and characterization of the recombinant enzyme | journal = The Journal of Biological Chemistry | volume = 275 | issue = 19 | pages = 14095–101 | date = May 2000 | pmid = 10799484 | doi = 10.1074/jbc.275.19.14095 | doi-access = free }}</ref> or phosphatidyl-bases.<ref name="pmid11481443">{{cite journal | vauthors = McNeil SD, Nuccio ML, Ziemak MJ, Hanson AD | title = Enhanced synthesis of choline and glycine betaine in transgenic tobacco plants that overexpress phosphoethanolamine N-methyltransferase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 17 | pages = 10001–5 | date = August 2001 | pmid = 11481443 | pmc = 55567 | doi = 10.1073/pnas.171228998 | bibcode = 2001PNAS...9810001M | doi-access = free }}</ref> The source of the methyl group is [[S-adenosyl-L-methionine|''S''-adenosyl-{{sc|L}}-methionine]] and [[S-adenosyl-L-homocysteine|''S''-adenosyl-{{sc|L}}-homocysteine]] is generated as a side product.<ref>{{cite web | title = Superpathway of choline biosynthesis | url = https://biocyc.org/META/NEW-IMAGE?object=PWY-4762 | work = BioCyc Database Collection: MetaCyc | publisher = SRI International }}</ref>

[[File:Choline metabolism.svg|thumb|300px|class=skin-invert-image|Main pathways of choline (Chol) metabolism, synthesis and excretion. Click for details. Some of the abbreviations are used in this section.]]

In humans and most other animals, de novo synthesis of choline proceeds via the [[phosphatidylethanolamine N-methyltransferase]] (PEMT) pathway,<ref name=eu/> but biosynthesis is not enough to meet human requirements.<ref name=his/> In the hepatic PEMT route, [[3-phosphoglycerate]] (3PG) receives 2 [[acyl group]]s from [[acyl-CoA]] forming a [[phosphatidic acid]]. It reacts with [[cytidine triphosphate]] to form cytidine diphosphate-diacylglycerol. Its [[hydroxyl group]] reacts with serine to form [[phosphatidylserine]] which [[decarboxylate]]s to ethanolamine and [[phosphatidylethanolamine]] (PE) forms. A PEMT enzyme moves three [[methyl]] groups from three [[S-adenosyl methionine|''S''-adenosyl methionines]] (SAM) donors to the ethanolamine group of the phosphatidylethanolamine to form choline in the form of a phosphatidylcholine. Three [[S-adenosyl homocysteine|''S''-adenosylhomocysteines]] (SAHs) are formed as a byproduct.<ref name=eu/>

Choline can also be released from more complex precursors. For example, [[phosphatidylcholine]]s (PC) can be hydrolyzed to choline (Chol) in most cell types. Choline can also be produced by the CDP-choline route, [[cytosolic]] [[choline kinase]]s (CK) phosphorylate choline with [[Adenosine triphosphate|ATP]] to [[phosphocholine]] (PChol).<ref name=ze/> This happens in some cell types like liver and kidney. [[Choline-phosphate cytidylyltransferase]]s (CPCT) transform PChol to [[CDP-choline]] (CDP-Chol) with cytidine triphosphate (CTP). CDP-choline and [[diglyceride]] are transformed to PC by [[diacylglycerol cholinephosphotransferase]] (CPT).<ref name=eu/>

In humans, certain PEMT-enzyme [[mutation]]s and [[estrogen deficiency]] (often due to [[menopause]]) increase the dietary need for choline. In rodents, 70% of phosphatidylcholines are formed via the PEMT route and only 30% via the CDP-choline route.<ref name=eu/> In [[knockout mice]], PEMT inactivation makes them completely dependent on dietary choline.<ref name=ze/>

=== Absorption ===
In humans, choline is absorbed from the [[intestine]]s via the [[SLC44A1]] (CTL1) [[membrane protein]] via [[facilitated diffusion]] governed by the choline concentration gradient and the electrical potential across the [[enterocyte]] membranes. SLC44A1 has limited ability to transport choline: at high concentrations part of it is left unabsorbed. Absorbed choline leaves the enterocytes via the [[portal vein]], passes the liver and enters [[systemic circulation]]. [[Gut microbe]]s degrade the unabsorbed choline to trimethylamine, which is oxidized in the liver to [[trimethylamine N-oxide|trimethylamine ''N''-oxide]].<ref name=eu/>

Phosphocholine and [[glycerophosphocholine]]s are hydrolyzed via [[phospholipase]]s to choline, which enters the portal vein. Due to their water solubility, some of them escape unchanged to the portal vein. Fat-soluble choline-containing compounds (phosphatidylcholines and [[sphingomyelin]]s) are either hydrolyzed by phospholipases or enter the [[lymph]] incorporated into [[chylomicron]]s.<ref name=eu/>

=== Transport ===
In humans, choline is transported as a free ion in blood. Choline–containing [[phospholipid]]s and other substances, like glycerophosphocholines, are transported in blood [[lipoprotein]]s. [[Blood plasma]] choline levels in healthy [[fasting]] adults is 7–20&nbsp;[[micromoles]] per liter (μmol/L) and 10&nbsp;μmol/L on average. Levels are regulated, but choline intake and deficiency alters these levels. Levels are elevated for about 3&nbsp;hours after choline consumption. Phosphatidylcholine levels in the plasma of fasting adults is 1.5–2.5&nbsp;mmol/L. Its consumption elevates the free choline levels for about 8–12&nbsp;hours, but does not affect phosphatidylcholine levels significantly.<ref name=eu/>

Choline is a water-soluble [[ion]] and thus requires transporters to pass through fat-soluble [[cell membrane]]s. Three types of choline transporters are known:<ref name="Inazu_2019" />
* [[SLC5A7]]
* CTLs: CTL1 ([[SLC44A1]]), CTL2 ([[SLC44A2]]) and CTL4 ([[SLC44A4]])
* OCTs: OCT1 ([[SLC22A1]]) and OCT2 ([[SLC22A2]])

SLC5A7s are [[sodium]]- (Na<sup>+</sup>) and ATP-dependent transporters.<ref name="Inazu_2019">{{cite journal | vauthors = Inazu M | title = Functional Expression of Choline Transporters in the Blood-Brain Barrier | journal = Nutrients | volume = 11 | issue = 10 | pages = 2265 | date = September 2019 | pmid = 31547050 | pmc = 6835570 | doi = 10.3390/nu11102265 | doi-access = free }}</ref><ref name=eu/> They have high [[binding affinity]] for choline, transport it primarily to [[neuron]]s and are indirectly associated with the [[acetylcholine]] production.<ref name=eu/> Their deficient function causes [[hereditary]] weakness in the pulmonary and other muscles in humans via acetylcholine deficiency. In [[knockout mice]], their dysfunction results easily in death with [[cyanosis]] and [[paralysis]].<ref>{{cite journal | vauthors = Barwick KE, Wright J, Al-Turki S, McEntagart MM, Nair A, Chioza B, Al-Memar A, Modarres H, Reilly MM, Dick KJ, Ruggiero AM, Blakely RD, Hurles ME, Crosby AH | title = Defective presynaptic choline transport underlies hereditary motor neuropathy | journal = American Journal of Human Genetics | volume = 91 | issue = 6 | pages = 1103–7 | date = December 2012 | pmid = 23141292 | pmc = 3516609 | doi = 10.1016/j.ajhg.2012.09.019 }}</ref>

CTL1s have moderate affinity for choline and transport it in almost all tissues, including the intestines, liver, kidneys, [[placenta]], and [[mitochondria]]. CTL1s supply choline for phosphatidylcholine and [[trimethylglycine]] production.<ref name=eu/> CTL2s occur especially in the mitochondria in the tongue, kidneys, muscles, and heart. They are associated with the mitochondrial [[oxidation]] of choline to trimethylglycine. CTL1s and CTL2s are not associated with the acetylcholine production, but transport choline together via the [[blood–brain barrier]]. Only CTL2s occur on the brain side of the barrier. They also remove excess choline from the neurons back to blood. CTL1s occur only on the blood side of the barrier, but also on the membranes of [[astrocyte]]s and neurons.<ref name="Inazu_2019" />

OCT1s and OCT2s are not associated with the acetylcholine production.<ref name=eu/> They transport choline with low affinity. OCT1s transport choline primarily in the liver and kidneys while  OCT2s transport choline in kidneys and the brain.<ref name="Inazu_2019" />

=== Storage ===
Choline is stored in the cell membranes and [[organelle]]s as phospholipids, and inside cells as phosphatidylcholines and glycerophosphocholines.<ref name=eu/>

=== Excretion ===
Even at choline doses of 2–8&nbsp;g, little choline is excreted into urine in humans. Excretion happens via transporters that occur within kidneys (see [[Choline#Transport|transport]]). Trimethylglycine is demethylated in the liver and kidneys to [[dimethylglycine]] ([[tetrahydrofolate]] receives one of the methyl groups). [[Methylglycine]] forms, is excreted into urine, or is demethylated to [[glycine]].<ref name=eu/>