Developing Synthetic Enzymes to Treat Inborn Errors of Metabolism

项目摘要。 支链酮酸对发育和神经的严重、急性和慢性影响 脱氢酶缺陷性枫糖浆尿病与异戊酰辅酶A 新生儿脱氢酶缺陷性异戊酸血症(IVD缺陷性IVA)是由于存在 它们的体内含有高浓度的亮氨酸、异亮氨酸和缬氨酸。患有这些疾病的患者是有限的 通过低蛋白质饮食和营养补充来管理他们的状况，这通常是不够的， 很难坚持，而且仍然可能导致代谢失调。管理策略包括减少 以及限制有毒代谢物和底物，促进合成代谢和刺激残留酶 活性以及激活氨基酸和酮酸清除途径。即使到了那时，中国人的生活质量 病人很穷，他们的照顾者也是如此，因为病人需要被密切监测以避免代谢危机 由感染、饮食或其他原因引起的。因此，对新药的需求非常大。 可使婴儿、儿童、青少年和成年人受益。这项工作是基于这样一个假设，即高度系统性 在某种程度上，使用高活性的酶可以降低患者体内有害氨基酸(S)的浓度 比如Pegvaliase如何降低苯丙酮尿症(PKU)患者的苯丙氨酸浓度。这项工作的核心 是一种双重方法的实现，它结合了实验性的定向进化技术和 计算酶设计。

Project Summary. The severe, acute, and chronic developmental and neurological impacts seen in branched chain ketoacid dehydrogenase deficient Maple Syrup Urine Disease (BCKD-deficient MSUD) and isovaleryl‐CoA dehydrogenase deficient Isovaleric Acidemia (IVD-deficient IVA) seen in newborns are due to the presence of high concentrations of leucine, isoleucine, and valine in their system. Patients with these disorders are limited to manage their condition though a low-protein diet and nutrient supplementation, which is often inadequate, difficult to adhere to, and can still lead to metabolic decompensation. Management strategies include reduction and restriction of toxic metabolites and substrates, promotion of anabolism and stimulation of residual enzyme activity along with activation of amino acid and ketoacid scavenging pathways. Even then, the quality of life of patients is poor, as is for their caregivers since patients need to be monitored closely to avoid metabolic crisis precipitated either by infection, diet, or other reasons. Thus, there is significant need for new medications that can benefit infants, children, adolescents, and adults. This work is based on the hypothesis that high systemic concentrations of offending amino acid(s) in patients can be reduced using high activity enzymes, in a manner like how Pegvaliase reduces phenylalanine concentrations in phenylketonuria (PKU) patients. Core to this work is implementation of a twofold approach that combines experimental directed evolution techniques and computations enzyme design.