HMBS Human

HMBS is involved in the third step of the heme biosynthetic pathway. It catalyzes the head-to-tail condensation of four porphobilinogen (PBG) molecules into the linear tetrapyrrole, hydroxymethylbilane (HMB), while releasing four ammonia molecules . The overall reaction can be summarized as follows:

$$4 \text{PBG} + \text{H}_2\text{O} \rightarrow \text{HMB} + 4 \text{NH}_3$$

The enzyme is highly conserved among organisms and consists of three domains. Domains 1 and 2 are structurally similar, each comprising five beta-sheets and three alpha helices. Domain 3, positioned between the other two, has a flattened beta-sheet geometry. A dipyrrole cofactor, consisting of two condensed PBG molecules, is covalently attached to domain 3 and extends into the active site, which is the cleft between domains 1 and 2 .

HMBS plays a vital role in the biosynthesis of heme, an essential component of hemoglobin, myoglobin, and various cytochromes. The enzyme’s activity is crucial for the proper functioning of these heme-containing proteins, which are involved in oxygen transport, storage, and electron transfer processes .

Mutations in the HMBS gene can lead to a condition known as acute intermittent porphyria (AIP), an autosomal-dominant disorder characterized by life-threatening neurovisceral attacks. These mutations can impair the enzyme’s function, leading to the accumulation of toxic intermediates in the heme biosynthetic pathway .

Recombinant HMBS is produced using genetic engineering techniques, where the HMBS gene is cloned and expressed in a suitable host organism, such as bacteria or yeast. This allows for the large-scale production of the enzyme for research and therapeutic purposes. Recombinant HMBS is used in various studies to understand the enzyme’s structure, function, and role in diseases like AIP .

Recent studies have focused on the molecular dynamics of HMBS, particularly the stepwise polymerization of PBG molecules and the specific roles of active-site residues in the enzymatic mechanism. These studies have provided insights into the enzyme’s catalytic process and the molecular basis of mutations causing AIP .