Tyrosine metabolism and formation of succinylacetone

In hepatorenal tyrosinemia, a defect in the enzyme fumarylacetoacetate hydratase (FAH) (step 6 in the figure), results in an increase in precursors in the pathway, ie, fumarylacetoacetate and maleylacetoacetate. Under these pathological conditions, these two chemicals can combine to form succinylacetoacetate and accinylacetone (lower right in figure), neither of which occurs in significant amounts under normal conditions. Succinylacetone is not synthesized with other disorders of tyrosine metabolism (which do not accumulate fumarylacetoacetate and maleylacetoacetate), and consequently elevations of succinylacetone are used in newborn screening for hepatorenal tyrosinemia, and elevations are pathognomonic for hepatorenal tyrosinemia. Succinylacetone is a potent inhibitor of porphobilinogen synthase, and this secondary enzyme inhibition links hepatorenal tyrosinemia with porphyrin/heme metabolism. (Source: Kitagawa 2012. Creative Commons Attribution License.)