Physiological function of enzyme ALAS2

In vertebrate organisms, there are two genes encoding ALAS enzymes that belong to α-oxoamine synthase family of pyridoxalphosphate(PLP)-dependent enzymes^[1]. ALAS1 is a house-keeping gene expressed ubiquitously, in contrast ALAS2 (gene location Xp11.21) is specific for erythroid progenitor cells^[2]. Both catalyze initial step in biosynthesis of heme cofactor. While the heme cofactor associated with proteins is essential for several physiological processes, for example transport of oxygen in red blood cells, free heme is toxic and perturbations in its metabolic pathway resulting in accumulation of intermediates lead to various blood diseases^{[3] [4]}.

ALAS role in heme biosynthesis

The initial and final steps of 8-step heme biosynthetic pathway take place in the mitochondrial matrix. Since the ALAS mediate first reaction it is rate-limiting enzyme regulating the whole pathway, also known as a gatekeeper^[5]. It catalyzes PLP-dependent condensation of glycine and succinyl-CoA forming 5-aminolevulinic acid (ALA)^[6]. ALA is then transported to cytoplasm where it undergoes subsequent reactions and eventually moves back to the mitochondria to form heme^[7].

The underlying mechanism of the ALAS enzymatic reaction is induced-fit substrate binding via open-to-close conformational transition. At first, the glycine substrate binds to PLP, an active form of vitamin B6, creating an external aldimine. Following deprotonation of glycine enable nucleophilic attack on the second substrate succinyl-CoA. Consequent condensation and decarboxylation form the ALA product. The product release relies on regeneration of an internal aldimine between PLP and ALAS protein^[8].

Structure of human ALAS2

ALAS2 enzyme is an obligatory homodimer. The interface between two monomeric subunits contains two active sites. In the absence of the substrate each active site, specifically its catalytic lysine residue (Lys391), bounds one PLP molecule. There are three domains within one human ALAS2 monomer. That is N-terminal domain (Met1-Val142) which contains mitochondrial targeting sequence, conserved catalytic core (Phe143-Gly544) and C-terminal domain (Leu545-Ala587) which is specific for eukaryotes^{[9] [10]}.

The conserved catalytic core can be further divided into glycine-rich motif (His219-Ile229) and active site loop (Tyr500-Arg517)^[11]. This loop plays a critical role in regulation of product release, since it interacts with the autoinhibitory C-terminal domain forming a regulatory gate . The regulation of the enzyme is further imposed by a particular alpha-helix (Ser568-Phe575) which residues Glu569 and Glu571 form salt bridge network with Asp159 and Arg511 (Figure 1C-D). The network establishes the closed state preventing the transition to the open state, in other words, it blocks the PLP-bounded active site^[12].

Mutations causing blood diseases

X-linked sideroblastic anemia

X-linked protoporphyria

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