Aspartokinase I-homoserine dehydrogenase I (AK I-HSD I) (AK I-HSD I)

Aspartokinase I-homoserine dehydrogenase I (AK I-HSD I) is a pivotal bifunctional enzyme in the aspartate-derived amino acid biosynthetic pathway, found in bacteria, fungi, and plants but absent in humans [UniProt P00561]. It catalyzes the first committed step of the pathway—the phosphorylation of L-aspartate to L-4-phosphoaspartate—as well as the third step, the reduction of L-aspartate-4-semialdehyde to L-homoserine [KEGG ec:2.7.2.4]. This enzyme is essential for the production of the aspartate family of amino acids, including threonine, methionine, and isoleucine, which are vital for protein synthesis and cell growth [PubMed 25663131]. AK I-HSD I is highly regulated through allosteric feedback inhibition by L-threonine, which binds to a specific regulatory domain to modulate catalytic activity [PubMed 15659344]. Due to its essentiality in pathogens and its absence in the human proteome, it is a significant target for the development of novel antibiotics and herbicides [PubMed 25663131]. Inhibiting this enzyme leads to amino acid starvation and bacterial death, offering a potential solution for treating multi-drug resistant infections [PubMed 25663131]. However, drug development must address the challenge of maintaining the host's beneficial microbiome, as many commensal bacteria also utilize this pathway [PubMed 25663131].

Other names

thrAAspartokinase 1AK IBifunctional aspartokinase/homoserine dehydrogenase 1AK-HSD I

Allosteric inhibition of the first committed step in the aspartate-derived amino acid biosynthetic pathway, preventing the formation of L-4-phosphoaspartate and subsequent essential amino acids [PubMed 15659344].