Vitamin C: Why We're Among the Few Mammals That Can't Make It

The mutation that made us depend on citrus

Most mammals make their own vitamin C in the liver (or, in some species, the kidney), without ever eating an orange. Scaled to a body weight of 70 kg, many species are estimated to produce several grams of ascorbic acid a day, and some increase production under stress.

Humans can do none of this. We make exactly zero milligrams of vitamin C, even though we carry almost all the genes for the synthesis pathway. The problem is the last step: the gene for L-gulonolactone oxidase (GULO), the enzyme that converts L-gulonolactone into ascorbic acid, has been inactive in our lineage for roughly 61 million years.

The original mutation was probably neutral or nearly so in a population of primates that ate vitamin C-rich fruit all the time. With no selective pressure against it, the GULO gene accumulated further mutations until it became a pseudogene: still recognisable as a relative of the working GULO of other mammals, but unable to produce active enzyme.

Structure: an enolic lactone built to donate electrons

Ascorbic acid (C₆H₈O₆) is a γ-lactone (a five-membered ring containing an oxygen) derived from glucose. Its most important structural feature is the enediol system at C-2 and C-3: two –OH groups attached to a C=C double bond, a unit that is particularly easy to oxidise.

This enediol system is the source of all of ascorbic acid's chemistry:

Two pKa values. The –OH at C-3 (pKa = 4.17) is unusually acidic for an alcohol, because the resulting negative charge is stabilised by resonance with the enediol and the lactone carbonyl. The –OH at C-2 (pKa = 11.57) is much less acidic. At physiological pH (7.4), ascorbic acid exists almost entirely as the ascorbate anion (charge −1).

Step-by-step oxidation. Ascorbate can give up one electron (and a proton) to form the semidehydroascorbate radical (also called the ascorbyl radical), which is unusually stable for an organic radical because the unpaired electron is spread over the enediol system. This radical can give up a second electron to form dehydroascorbate (DHA), the fully oxidised form.

Ascorbate → Ascorbyl radical → Dehydroascorbate

The stability of that intermediate radical is why vitamin C is such an effective antioxidant: instead of starting chain reactions as many radicals do, the ascorbyl radical is calm enough to be regenerated by enzymes or simply to end the radical chain harmlessly.

Function 1: making collagen

Vitamin C is an indispensable cofactor for two enzymes in collagen synthesis: prolyl hydroxylase and lysyl hydroxylase. They convert proline and lysine residues in procollagen into hydroxyproline and hydroxylysine, post-translational modifications essential for forming the collagen triple helix, which is held together by hydrogen bonds.

Without vitamin C, the hydroxylases lose their active Fe²⁺ cofactor: in some cycles the reaction becomes uncoupled, the iron is left oxidised as Fe³⁺, and only ascorbate can bring it back to Fe²⁺. Without hydroxyproline the collagen triple helix does not form properly, and the faulty collagen cannot assemble into the fibres that give strength to skin, blood vessels, gums and bones.

The result is scurvy, the disease that devastated ships' crews from the 15th to the 18th centuries. Its symptoms (bleeding gums, wounds that will not heal, loose teeth, haemorrhages) are exactly what you would expect from a general collapse of collagen synthesis. Symptoms appear after 1–3 months without vitamin C, and untreated the disease is fatal.

Function 2: absorbing non-haem iron

Iron from plant foods (non-haem iron) reaches the gut as Fe³⁺, a form that intestinal cells absorb poorly. Vitamin C in the gut reduces Fe³⁺ to Fe²⁺, which is actively taken up by DMT-1 (divalent metal transporter 1).

The effect is quantitatively important: a source of vitamin C eaten together with an iron-rich vegetarian meal (lentils, spinach) can increase non-haem iron absorption 2 to 4 times. Ascorbic acid also counteracts the inhibitory effect of phytates and tea polyphenols on iron absorption.

For people at risk of iron-deficiency anaemia, especially vegetarians, combining plant iron sources with vitamin C is not an optional detail but a nutritional intervention backed by solid evidence.

Function 3: water-phase antioxidant and vitamin E recycler

Vitamin C is the most important water-soluble antioxidant in plasma and in the fluid inside cells, complementing vitamin E (α-tocopherol), which works in lipid membranes. This division of labour is no accident: free radicals generated in membranes are captured by vitamin E, which becomes the tocopheryl radical; that radical moves to the membrane-water interface, where ascorbate reduces it back to active tocopherol.

This regeneration of vitamin E by vitamin C completes a coordinated antioxidant cycle that protects both the watery and the fatty phases. Without vitamin C, vitamin E is left stuck in its radical form, which can even be pro-oxidant. The synergy between the two vitamins is therefore two-way and essential.

The antioxidant paradox: can vitamin C do harm?

In the presence of free iron (unbound Fe²⁺ or Fe³⁺), ascorbate can act as a pro-oxidant: the Fenton reaction generates the hydroxyl radical (·OH) from hydrogen peroxide, one of the most reactive and damaging radicals known.

Fe²⁺ + H₂O₂ → Fe³⁺ + ·OH + OH⁻

In the test tube, high concentrations of vitamin C plus free iron cause massive oxidative damage. In the body, however, free iron hardly exists: it is always bound to proteins (ferritin, transferrin, haemoglobin). In normal tissues, vitamin C's pro-oxidant effect is minimal.

Things change in haemochromatosis (pathological iron overload) and in some cancers (where intracellular iron may be partly free). In these specific contexts, megadose vitamin C supplements may be harmful, although high-dose intravenous vitamin C is also being studied as an add-on to chemotherapy precisely to exploit its pro-oxidant effect in the iron-rich tumour environment.

How much vitamin C do we need?

The recommended daily intake in the USA is 75–90 mg for adults (95–110 mg in the EU), enough to prevent scurvy with a wide margin. The tolerable upper intake level (UL) is 2,000 mg a day.

Blood levels saturate at around 200–400 mg a day: above that, intestinal absorption falls and kidney excretion rises, limiting any further increase in plasma. That is why megadose supplements (1,000–3,000 mg a day) raise blood levels only modestly compared with moderate doses: the "excess" is simply lost in urine.

Smokers need about 35 mg a day more because tobacco's oxidative stress uses up vitamin C faster. People undergoing major surgery, with extensive burns or severe infections also need more, as collagen synthesis and the immune response in those conditions consume ascorbate rapidly.

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