Figure 2.

Different regulation of the housekeeping (ALAS1) and erythroid (ALAS2) forms of 5-aminolevulinate synthase.

Notes: The two isozymes for ALAS are encoded by separate genes (ALAS1 on chromosome 3 and ALAS2 on the X chromosome), and provide ALA for eventual heme for hemoproteins and other cellular needs. The genes are uniquely induced and repressed in varying tissues.2,55 (A) The C terminal polypeptide sequence of human ALAS2 with mutation sites (red) known to contribute to XLPP. (B) bp sequence of human ALAS2 spanning known deletion (red) polymorphisms resulting in gain of function. The truncated bp sequences of the XLPP mutants are also displayed with amino acid substitutions. (C) Differential location and regulation of ALAS1 vs ALAS2 are reflected in the potential resulting porphyrias manifested when there is uncontrolled upregulation of the respective genes. Heme markedly downregulates (red) ALAS1, acting at several different levels.2 In contrast, heme has little if any down-regulatory effect on ALAS2, but this gene is upregulated by iron acting through iron regulatory proteins to increase translation and downregulated by lack of iron in developing red blood cells, such that a balance is normally retained between PP synthesis and availability of iron for heme and hemoglobin formation.2,55 Upregulation (green) of either ALAS1 (chemicals) or ALAS2 (gain-of-function mutations) leads to different forms of porphyria (acute porphyrias or XLPP).

Abbreviations: XLPP, X-linked protoporphyria; bp, base pair; ALAS, 5-aminolevulinate synthase; PP, protoporphyrin; WT, wild type.