Orotate (OA) is well-known as a precursor in biosynthesis of
pyrimidines; in mammals it is released from the mitochondrial
dihydroorotate dehydrogenase (
DHODH) for conversion to
UMP by the cytoplasmic
UMP synthase enzyme. OA is also a normal part of the diet, being found in milk and dairy products, and it is converted to
uridine for use in the
pyrimidine salvage pathway predominantly in liver, kidney and erythrocytes. Early research into nutrition identified orotate as "
vitamin B13," and its use as a complex with organic
cations or
metal ions was promulgated in body-building, and in assisting
therapies of
metabolic syndromes. It has recently been established that the amelioration of
gout by dairy products arises from the competition of orotate and
urate at the hURAT1 transporter. The orotic aciduria that arises in children with defective
UMP synthase can be rescued by oral
uridine therapy, since
UMP is the end-product and also a feedback inhibitor of the de novo pathway. In contrast, Miller (dysmorphology) syndrome is connected with defects in
DHODH, and hence in the supply of OA, and cannot be helped by
uridine. Other models of dysmorphisms are connected with
enzymes early in the
pyrimidine de novo pathway. We conclude that the OA molecule is itself required for the regulation of genes that are important in the development of cells, tissues and organisms.