Succinylacetone

Succinylacetone is an inhibitor of δ-aminolevulinic acid dehydratase (K_i = 300 nM for human erythrocyte enzyme).¹ It inhibits heme biosynthesis and decreases the growth of murine erythroleukemia cells when used at concentrations of 0.1 and 1 mM.² Succinylacetone is an abnormal metabolite of tyrosine that accumulates in hereditary tyrosinemia type I, a disorder characterized by a deficiency in fumarylacetoacetate hydrolase (FAH), the final enzyme in tyrosine catabolism.³ Without functional FAH, fumarylacetoacetate is converted into succinylacetone. In a rat model of hypertyrosinemia, succinylacetone (40 mg/kg twice daily) increases levels of δ-aminolevulinic acid in urine, decreases heme levels in liver, kidney, spleen, and vascular tissues, and reduces sensitivity of isolated rat aortic rings to endothelium-dependent and -independent vasodilation. Increased levels of succinylacetone has been used as a marker of tyrosinemia type 1.⁴

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1. Sassa, S., and Kappas, A. Hereditary tyrosinemia and the heme biosynthetic pathway. Profound inhibition of delta-aminolevulinic acid dehydratase activity by succinylacetone. J. Clin. Invest. 71(3), 625-634 (1983).

2. Ebert, P.S., Hess, R.A., Frykholm, B.C., et al. Succinylacetone, a potent inhibitor of heme biosynthesis: effect on cell growth, heme content and delta-aminolevulinic acid dehydratase activity of malignant murine erythroleukemia cells. biochem. Biophys. Res. Commun. 88(4), 1382-1390 (1979).

3. Moore, M.E., Koenig, A.E., Hilgartner, M.A., et al. Abnormal social behavior in mice with tyrosinemia type I is associated with an increase of myelin in the cerebral cortex. Metab. Brain Dis. 32(6), 1829-1841 (2017).

4. Stinton, C., Geppert, J., Greeman, K., et al. Newborn screening for Tyrosinemia type 1 using succinylacetone - a systematic review of test accuracy. Orphanet J. Rare Dis. 12(1), 48 (2017).