Department of Organic Synthesis, Institute of the Chemistry of Plant Substances, Building 77, Acad. Kh. Abdullaev Str., 100170 Tashkent, Uzbekistan.
Amino Acids. 2012 Nov;43(5):2015-25. doi: 10.1007/s00726-012-1276-0. Epub 2012 Mar 27.
This study presents a design of a highly potent and competitive inhibitory peptide for 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). HMGR is the major regulatory enzyme of cholesterol biosynthesis and the target enzyme of many investigations aimed at lowering the rate of cholesterol biosynthesis. In previous studies, the two hypocholesterolemic peptides (LPYP and IAVPGEVA) were isolated and identified from soy protein. Based on these peptide sequences, a number of peptides were designed previously by using the correlation between the conformational flexibility and bioactivity. The design method that was applied in previous studies was slightly modified for the purpose of the current research and 12 new peptides were designed and synthesized. Among all peptides, SFGYVAE showed the highest ability to inhibit HMGR. A kinetic analysis revealed that this peptide is a competitive inhibitor of HMG-CoA with an equilibrium constant of inhibitor binding (K (i)) of 12 ± 0.4 nM. This is an overall 14,500-fold increase in inhibitory activity compared to the first isolated LPYP peptide from soybeans. Conformational data support a conformation of the designed peptides close to the bioactive conformation of the previously synthesized active peptides.
本研究设计了一种对 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGR）具有高活性和竞争力的抑制肽。HMGR 是胆固醇生物合成的主要调节酶，也是许多旨在降低胆固醇生物合成速率的研究的靶酶。在以前的研究中，两种降胆固醇肽（LPYP 和 IAVPGEVA）已从大豆蛋白中分离并鉴定出来。基于这些肽序列，以前曾使用构象灵活性和生物活性之间的相关性来设计许多肽。为了进行当前的研究，略微修改了以前研究中应用的设计方法，并设计和合成了 12 种新肽。在所有肽中，SFGYVAE 显示出最强的抑制 HMGR 的能力。动力学分析表明，该肽是 HMG-CoA 的竞争性抑制剂，其抑制剂结合平衡常数（K（i））为 12±0.4 nM。与最初从大豆中分离的 LPYP 肽相比，这使抑制活性总体提高了 14500 倍。构象数据支持设计肽的构象接近先前合成的活性肽的生物活性构象。
