Editing Vitamin C (section)

=== Animal synthesis ===
There is some information on serum vitamin C concentrations maintained in animal species that are able to synthesize vitamin C. One study of several breeds of dogs reported an average of 35.9&nbsp;μmol/L.<ref name="pmid11666145">{{cite journal |vauthors=Wang S, Berge GE, Sund RB |title=Plasma ascorbic acid concentrations in healthy dogs |journal=Res. Vet. Sci. |volume=71 |issue=1 |pages=33–5 |date=August 2001 |pmid=11666145 |doi=10.1053/rvsc.2001.0481 }}</ref> A report on goats, sheep and cattle reported ranges of 100–110, 265–270 and 160–350&nbsp;μmol/L, respectively.<ref name=Ranjan2012>{{cite journal |vauthors=Ranjan R, Ranjan A, Dhaliwal GS, Patra RC |s2cid=1674389 |title=l-Ascorbic acid (vitamin C) supplementation to optimize health and reproduction in cattle |journal=Vet Q |volume=32 |issue=3–4 |pages=145–50 |date=2012 |pmid=23078207 |doi=10.1080/01652176.2012.734640 }}</ref>

The biosynthesis of ascorbic acid in [[vertebrates]] starts with the formation of UDP-glucuronic acid. UDP-glucuronic acid is formed when UDP-glucose undergoes two oxidations catalyzed by the enzyme UDP-glucose 6-dehydrogenase. UDP-glucose 6-dehydrogenase uses the co-factor NAD<sup>+</sup> as the electron acceptor. The transferase UDP-glucuronate pyrophosphorylase removes a [[Uridine monophosphate|UMP]] and [[glucuronokinase]], with the cofactor ADP, removes the final phosphate leading to [[glucuronic acid|{{sm|d}}-glucuronic acid]]. The aldehyde group of this compound is reduced to a primary alcohol using the enzyme [[glucuronate reductase]] and the cofactor NADPH, yielding {{sm|l}}-gulonic acid. This is followed by lactone formation{{Em dash}}utilizing the hydrolase [[gluconolactonase]]{{Em dash}}between the carbonyl on C1 and hydroxyl group on C4. {{sm|l}}-Gulonolactone then reacts with oxygen, catalyzed by the enzyme [[L-gulonolactone oxidase]] (which is nonfunctional in humans and other [[Haplorrhini]] primates; see [[Pseudogene#Unitary pseudogenes|Unitary pseudogenes]]) and the cofactor FAD+. This reaction produces 2-oxogulonolactone (2-keto-gulonolactone), which spontaneously undergoes [[enolization]] to form ascorbic acid.<ref name="Stone" /><ref name="West Sussex 2009">{{cite book | vauthors = Dewick PM | title = Medicinal natural products: a biosynthetic approach | edition = 3rd | year = 2009 | isbn = 978-0-470-74167-2 | publisher = John Wiley and Sons | page = 493}}</ref><ref name=Linster2007>{{cite journal | vauthors = Linster CL, Van Schaftingen E | title = Vitamin C. Biosynthesis, recycling and degradation in mammals | journal = The FEBS Journal | volume = 274 | issue = 1 | pages = 1–22 | date = January 2007 | pmid = 17222174 | doi = 10.1111/j.1742-4658.2006.05607.x | s2cid = 21345196 | doi-access = free | title-link = doi }}</ref> Reptiles and older orders of birds make ascorbic acid in their kidneys. Recent orders of birds and most mammals make ascorbic acid in their liver.<ref name="Stone" />

====Non-synthesizers====
Some mammals have lost the ability to synthesize vitamin C, including [[simian]]s and [[tarsier]]s, which together make up one of two major [[primate]] suborders, [[Haplorhini]]. This group includes humans. The other more primitive primates ([[Strepsirrhini]]) have the ability to make vitamin C. Synthesis does not occur in some species in the rodent family [[Caviidae]], which includes [[guinea pig]]s and [[capybara]]s, but does occur in other rodents, including [[rat]]s and [[mouse|mice]].<ref name="Miller-2014">{{cite book | vauthors = Miller RE, Fowler ME | title = Fowler's zoo and wild animal medicine, volume 8 | page = 389 | url = https://books.google.com/books?id=llBcBAAAQBAJ&q=Caviidae+%22vitamin+C%22&pg=PA389 |access-date=2 June 2016 |url-status=live |archive-url=https://web.archive.org/web/20161207032904/https://books.google.com/books?id=llBcBAAAQBAJ&pg=PA389&lpg=PA389&dq=Caviidae+%22vitamin+C%22&source=bl&ots=ofF-Bu-mx-&sig=nPEZZ68O7v26lmGS9eAGfmaUZ1o&hl=en&sa=X&ved=0ahUKEwiIk471gInNAhUT0WMKHWlpAqAQ6AEISDAH#v=onepage&q=Caviidae%20%22vitamin%20C%22&f=false |archive-date=December 7, 2016 | isbn = 978-1-4557-7399-2 |date=2014 | publisher = Elsevier Health Sciences }}</ref>

Synthesis does not occur in most bat species,<ref name="Jenness-1980">{{cite journal |doi=10.1016/0305-0491(80)90131-5 |title=Variation of l-gulonolactone oxidase activity in placental mammals |year=1980 |vauthors=Jenness R, Birney E, Ayaz K |journal=Comparative Biochemistry and Physiology B |volume=67 |issue=2 |pages=195–204 }}</ref> but there are at least two species, frugivorous bat ''[[Rousettus leschenaultii]]'' and insectivorous bat ''[[Hipposideros armiger]]'', that retain (or regained) their ability of vitamin C production.<ref name="pmid21037206">{{cite journal | vauthors = Cui J, Pan YH, Zhang Y, Jones G, Zhang S | title = Progressive pseudogenization: vitamin C synthesis and its loss in bats | journal = Molecular Biology and Evolution | volume = 28 | issue = 2 | pages = 1025–31 | date = February 2011 | pmid = 21037206 | doi = 10.1093/molbev/msq286 | doi-access = free | title-link = doi }}</ref><ref name="pmid22069493">{{cite journal | vauthors = Cui J, Yuan X, Wang L, Jones G, Zhang S | title = Recent loss of vitamin C biosynthesis ability in bats | journal = PLOS ONE | volume = 6 | issue = 11 | pages = e27114 | date = Nov 2011 | pmid = 22069493 | pmc = 3206078 | doi = 10.1371/journal.pone.0027114 | doi-access = free | title-link = doi | bibcode = 2011PLoSO...627114C }}</ref> A number of species of passerine birds also do not synthesize, but not all of them, and those that do not are not clearly related; it has been proposed that the ability was lost separately a number of times in birds.<ref name="Martinez del Rio_1997">{{cite journal |title=Can passerines synthesize vitamin C? | vauthors = Martinez del Rio C |journal= The Auk |date=July 1997 |volume=114 |issue=3 |pages=513–6 |jstor=4089257 |doi=10.2307/4089257 | doi-access = free | title-link = doi }}</ref> In particular, the ability to synthesize vitamin C is presumed to have been lost and then later re-acquired in at least two cases.<ref name="pmid22294879">{{cite journal | vauthors = Drouin G, Godin JR, Pagé B | title = The genetics of vitamin C loss in vertebrates | journal = Current Genomics | volume = 12 | issue = 5 | pages = 371–8 | date = August 2011 | pmid = 22294879 | pmc = 3145266 | doi = 10.2174/138920211796429736 }}</ref> The ability to synthesize vitamin{{nbsp}}C has also been lost in about 96% of [[Extant taxon|extant]] fish<ref name=Berra>{{cite book | vauthors = Berra TM |title=Freshwater fish distribution |url=https://books.google.com/books?id=K-1Ygw6XwFQC&pg=PA55 |year=2008 |publisher=[[University of Chicago Press]] |isbn=978-0-226-04443-9|page=55}}</ref> (the [[teleosts]]).<ref name="pmid22294879" />

On a milligram consumed per kilogram of body weight basis, simian non-synthesizer species consume the vitamin in amounts 10 to 20 times higher than what is recommended by governments for humans.<ref name="pmid10378206">{{cite journal | vauthors = Milton K | title = Nutritional characteristics of wild primate foods: do the diets of our closest living relatives have lessons for us? | journal = Nutrition | volume = 15 | issue = 6 | pages = 488–98 | date = June 1999 | pmid = 10378206 | doi = 10.1016/S0899-9007(99)00078-7 | url = http://www.direct-ms.org/pdf/EvolutionPaleolithic/primaten.pdf | archive-url = https://web.archive.org/web/20170810090049/http://www.direct-ms.org/pdf/EvolutionPaleolithic/primaten.pdf | df = mdy-all | url-status = live | archive-date = 10 August 2017 | citeseerx = 10.1.1.564.1533}}</ref> This discrepancy constituted some of the basis of the controversy on human recommended dietary allowances being set too low.<ref name=pmid5275366 /> However, simian consumption does not indicate simian requirements. Merck's veterinary manual states that daily intake of vitamin C at 3–6&nbsp;mg/kg prevents scurvy in non-human primates.<ref name="Parrott-2022">{{cite web |url=https://www.msdvetmanual.com/exotic-and-laboratory-animals/nonhuman-primates/nutritional-diseases-of-nonhuman-primates |title=Nutritional diseases of nonhuman primates | vauthors = Parrott T |date=October 2022 |website=Merck Veterinary Manual |access-date=24 December 2023 |archive-date=December 24, 2023 |archive-url=https://web.archive.org/web/20231224173242/https://www.msdvetmanual.com/exotic-and-laboratory-animals/nonhuman-primates/nutritional-diseases-of-nonhuman-primates |url-status=live }}</ref> By way of comparison, across several countries, the recommended dietary intake for adult humans is in the range of 1–2&nbsp;mg/kg.

====Evolution of animal synthesis====
Ascorbic acid is a common enzymatic [[cofactor (biochemistry)|cofactor]] in mammals used in the synthesis of [[collagen]], as well as a powerful [[reducing agent]] capable of rapidly scavenging a number of [[reactive oxygen species]] (ROS). Given that ascorbate has these important functions, it is surprising that the ability to synthesize this molecule has not always been conserved. In fact, anthropoid primates, ''[[Guinea pig|Cavia porcellus]]'' (guinea pigs), [[teleost]] fishes, most bats, and some [[passerine]] birds have all independently lost the ability to internally synthesize vitamin C in either the kidney or the liver.<ref name="pmid21140195">{{cite journal | vauthors = Lachapelle MY, Drouin G | title = Inactivation dates of the human and guinea pig vitamin C genes | journal = Genetica | volume = 139 | issue = 2 | pages = 199–207 | date = February 2011 | pmid = 21140195 | doi = 10.1007/s10709-010-9537-x | s2cid = 7747147 }}</ref><ref name="pmid22294879"/> In all of the cases where genomic analysis was done on an ascorbic acid [[Auxotrophy|auxotroph]], the origin of the change was found to be a result of loss-of-function mutations in the gene that encodes <small>L</small>-gulono-γ-lactone oxidase, the enzyme that catalyzes the last step of the ascorbic acid pathway outlined above.<ref name="pmid23404229">{{cite journal | vauthors = Yang H | s2cid = 14393449 | title = Conserved or lost: molecular evolution of the key gene GULO in vertebrate vitamin C biosynthesis | journal = Biochemical Genetics | volume = 51 | issue = 5–6 | pages = 413–25 | date = June 2013 | pmid = 23404229 | doi = 10.1007/s10528-013-9574-0 }}</ref> One explanation for the repeated loss of the ability to synthesize vitamin C is that it was the result of [[genetic drift]]; assuming that the diet was rich in vitamin{{nbsp}}C, natural selection would not act to preserve it.<ref name="pmid20210993">{{cite journal | vauthors = Zhang ZD, Frankish A, Hunt T, Harrow J, Gerstein M | title = Identification and analysis of unitary pseudogenes: historic and contemporary gene losses in humans and other primates | journal = Genome Biology | volume = 11 | issue = 3 | pages = R26 | date = 2010 | pmid = 20210993 | pmc = 2864566 | doi = 10.1186/gb-2010-11-3-r26 | doi-access = free | title-link = doi }}</ref><ref name="pmid3338984">{{cite journal | vauthors = Koshizaka T, Nishikimi M, Ozawa T, Yagi K | title = Isolation and sequence analysis of a complementary DNA encoding rat liver L-gulono-gamma-lactone oxidase, a key enzyme for L-ascorbic acid biosynthesis | journal = The Journal of Biological Chemistry | volume = 263 | issue = 4 | pages = 1619–21 | date = February 1988 | doi = 10.1016/S0021-9258(19)77923-X | pmid = 3338984 | doi-access = free | title-link = doi }}</ref>

In the case of the simians, it is thought that the loss of the ability to make vitamin C may have occurred much farther back in evolutionary history than the emergence of humans or even apes, since it evidently occurred soon after the appearance of the first primates, yet sometime after the split of early primates into the two major suborders [[Haplorrhini]] (which cannot make vitamin C) and its sister suborder of non-tarsier prosimians, the [[Strepsirrhini]] ("wet-nosed" primates), which retained the ability to make vitamin C.<ref name="pmid3113259">{{cite journal | vauthors = Pollock JI, Mullin RJ | title = Vitamin C biosynthesis in prosimians: evidence for the anthropoid affinity of Tarsius | journal = American Journal of Physical Anthropology | volume = 73 | issue = 1 | pages = 65–70 | date=1987 | pmid = 3113259 | doi = 10.1002/ajpa.1330730106 }}</ref> According to molecular clock dating, these two suborder primate branches parted ways about 63 to 60 million years ago.<ref name="pmid15085543">{{cite journal | vauthors = Poux C, Douzery EJ | title = Primate phylogeny, evolutionary rate variations, and divergence times: a contribution from the nuclear gene IRBP | journal = American Journal of Physical Anthropology | volume = 124 | issue = 1 | pages = 01–16 | date=2004 | pmid = 15085543 | doi = 10.1002/ajpa.10322 }}</ref> Approximately three to five million years later (58 million years ago), only a short time afterward from an evolutionary perspective, the infraorder [[Tarsiiformes]], whose only remaining family is that of the tarsier ([[Tarsiidae]]), branched off from the other haplorrhines.<ref name="pmid9668008">{{cite journal | vauthors = Goodman M, Porter CA, Czelusniak J, Page SL, Schneider H, Shoshani J, Gunnell G, Groves CP | title = Toward a phylogenetic classification of Primates based on DNA evidence complemented by fossil evidence | journal = Molecular Phylogenetics and Evolution | volume = 9 | issue = 3 | pages = 585–98 | date=June 1998 | pmid = 9668008 | doi = 10.1006/mpev.1998.0495 | bibcode = 1998MolPE...9..585G | s2cid = 23525774 }}</ref><ref name="Porter_1997">{{cite journal |vauthors=Porter CA, Page SL, Czelusniak J, Schneider H, Schneider MP, Sampaio I, Goodman M |s2cid=1851788 |title=Phylogeny and evolution of selected primates as determined by sequences of the ε-globin locus and 5′ flanking regions |journal=Int J Primatol |date= April 1997 |volume=18 |issue=2 |pages=261–95 |doi=10.1023/A:1026328804319 |hdl=2027.42/44561 |hdl-access=free }}</ref> Since tarsiers also cannot make vitamin C, this implies the mutation had already occurred, and thus must have occurred between these two marker points (63 to 58 million years ago).<ref name="pmid3113259" />

It has also been noted that the loss of the ability to synthesize ascorbate strikingly parallels the inability to break down [[uric acid]], also a characteristic of primates. Uric acid and ascorbate are both strong [[reducing agent]]s. This has led to the suggestion that, in higher primates, uric acid has taken over some of the functions of ascorbate.<ref name="pmid5477017">{{cite journal | vauthors = Proctor P | s2cid = 4146946 | title = Similar functions of uric acid and ascorbate in man? | journal = Nature | volume = 228 | issue = 5274 | pages = 868 | date = 1970 | pmid = 5477017 | doi = 10.1038/228868a0 | bibcode = 1970Natur.228..868P | doi-access = free | title-link = doi }}</ref>