Department of Biomedicine, University of Bergen, Norway.
Norwegian Porphyria Centre (NAPOS), Department for Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway.
FEBS Open Bio. 2022 Dec;12(12):2136-2146. doi: 10.1002/2211-5463.13490. Epub 2022 Sep 26.
Hydroxymethylbilane synthase (HMBS) is the third enzyme involved in haem biosynthesis, in which it catalyses the formation of tetrapyrrole 1-hydroxymethylbilane (HMB). In this process, HMBS binds four consecutive substrate molecules, creating the enzyme-intermediate complexes ES, ES , ES and ES . Pathogenic variants in the HMBS gene are associated with the dominantly inherited disorder acute intermittent porphyria. In this study, we have characterised the p.R26H variant to shed light on the role of Arg26 in the elongation mechanism of HMBS and to provide insights into its effect on the enzyme. With selected biophysical methods, we have been able to show that p.R26H forms a single enzyme-intermediate complex in the ES -state. We were also able to demonstrate that the p.R26H variant results in an inactive enzyme, which is unable to produce the HMB product.
羟甲基胆素合酶（HMBS）是血红素生物合成中涉及的第三种酶，它催化四吡咯 1-羟甲基胆素（HMB）的形成。在此过程中，HMBS 结合四个连续的底物分子，形成酶中间复合物 ES、ES 、ES 和 ES 。HMBS 基因中的致病性变体与显性遗传疾病急性间歇性卟啉症有关。在这项研究中，我们对 p.R26H 变体进行了表征，以阐明 Arg26 在 HMBS 延伸机制中的作用，并深入了解其对酶的影响。通过选择的生物物理方法，我们能够表明 p.R26H 在 ES 状态下形成单个酶中间复合物。我们还能够证明 p.R26H 变体导致酶失活，无法产生 HMB 产物。
