About 70% of urate is endogenous and 30% comes from diet, and xanthine oxidase (XO) catalyzes the last two steps to urate.About 70% of urate is endogenous (cell turnover, energy metabolism); 30% from diet. The last two steps — hypoxanthine → xanthine → urate — are both catalyzed by xanthine oxidase (XO). Allopurinol and febuxostat work by inhibiting XO.
2 · Humans lost uricase
About 15 million years ago the uricase gene became a pseudogene in the hominid lineage, so humans cannot break urate into soluble allantoin and must excrete it as-is.Most mammals express uricase, which breaks urate into soluble allantoin. In the hominid lineage ~15 million years ago, the uricase gene became a pseudogene. Urate is now an end product in humans — we can only excrete it as-is.
3 · Excretion · 90% is under-excretion
Clinically, ~90% of hyperuricemia is under-excretion, not over-production.~2/3 goes via kidney, 1/3 via gut. Glomerular filtration is the same for everyone; the difference is in tubular reabsorption vs efflux transporters.
4 · Three gates · URAT1 · GLUT9 · ABCG2
URAT1 and GLUT9 reabsorb urate back into the blood, while ABCG2, the only active efflux pump, pushes it out.URAT1 (SLC22A12) is the main reabsorption gate; GLUT9 (SLC2A9) completes the return to blood; ABCG2 is the only active efflux pump (kidney + gut). ABCG2 loss-of-function variants are common in East Asians — a major genetic basis for early-onset hyperuricemia. Insulin activates URAT1 — which is why losing visceral fat beats avoiding seafood.