Regulation of cystathionine-beta-synthase (CBS) mediated hydrogen sulfide (H2S) production and its biological function

胱硫醚-β-合酶（CBS）介导的硫化氢（H2S）产生及其生物学功能的调节

• 批准号: 311587-2011
• 负责人: O, Karmin
• 金额: $ 2.62万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=506099
• 关键词: Regulation; cystathionine; beta; synthase; CBS

Homocysteine (Hcy) and hydrogen sulfide (H2S) are two important molecules produced in the body during the metabolism of sulfur amino acids (i.e. methionine, cysteine). Hcy is an intermediate amino acid produced through the conversion of essential amino acid methionine to cysteine. Hcy can either be regenerated to methionine as well as metabolized to cysteine or H2S. Cystathionine beta-synthase (CBS) is a key enzyme that regulates Hcy metabolism and H2S generation. Reduced CBS enzyme activity leads to (1) increased Hcy and (2) decreased H2S levels in the blood. CBS enzyme is present in several organs including the kidney that plays a key role in regulating sulfur amino acid and Hcy metabolism. It has long been known that too much Hcy in the circulation, a condition called hyperhomocysteinemia, can cause multiple organ injury. Hyperhomocysteinemia is often found in persons with kidney failure. One of the common causes of kidney failure is ischemia-reperfusion injury. Ischemia is a hypoxic condition with decreased or no blood flow to the tissue and reperfusion is the restoration of blood flow to the ischemic tissue. The affected tissue undergoes oxidative stress, a condition in which cells are damaged by reactive oxygen species. Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species and the detoxifying capability of antioxidant defense mechanisms. We have observed that ischemia-reperfusion causes a reduction of CBS enzyme activity leading to Hcy accumulation in the kidney. Hcy, in turn, stimulates the production of reactive oxygen species in the kidney causing oxidative stress and cell death. The H2S level in the kidney is severely decreased upon ischemia-reperfusion and is inversely associated with tissue damage. At physiological levels, H2S acts as a vasodilator and neurotransmitter. However, the biological function of H2S in the kidney is not well understood. In the proposed research, we aim to identify (1) the role that H2S plays in the kidney (2) whether regulation of H2S synthesis through restoration of CBS activity offers any protective effect against ischemia-reperfusion induced oxidative stress and kidney damage.

同型半胱氨酸（Hcy）和硫化氢（H2S）是体内含硫氨基酸（即蛋氨酸、半胱氨酸）代谢过程中产生的两种重要分子。 Hcy 是必需氨基酸蛋氨酸转化为半胱氨酸产生的中间氨基酸。 Hcy 可以再生为蛋氨酸，也可以代谢为半胱氨酸或 H2S。胱硫醚β-合酶（CBS）是调节Hcy代谢和H2S生成的关键酶。 CBS 酶活性降低会导致 (1) Hcy 升高和 (2) 血液中 H2S 水平降低。 CBS酶存在于包括肾脏在内的多个器官中，在调节硫氨基酸和Hcy代谢中发挥关键作用。人们早就知道，循环中过多的同型半胱氨酸（一种称为高同型半胱氨酸血症的疾病）会导致多器官损伤。高同型半胱氨酸血症常见于肾衰竭患者。肾衰竭的常见原因之一是缺血再灌注损伤。缺血是一种缺氧状况，组织血流减少或没有血流，再灌注是缺血组织血流恢复。受影响的组织会经历氧化应激，即细胞被活性氧损伤的情况。当活性氧的产生与抗氧化防御机制的解毒能力之间不平衡时，就会发生氧化应激。我们观察到缺血再灌注会导致 CBS 酶活性降低，导致 Hcy 在肾脏中积聚。 Hcy 反过来会刺激肾脏中活性氧的产生，导致氧化应激和细胞死亡。肾脏中的 H2S 水平在缺血再灌注时严重降低，并且与组织损伤呈负相关。在生理水平上，H2S 充当血管舒张剂和神经递质。然而，H2S 在肾脏中的生物学功能尚不清楚。在拟议的研究中，我们的目标是确定 (1) H2S 在肾脏中发挥的作用 (2) 通过恢复 CBS 活性来调节 H2S 合成是否对缺血再灌注引起的氧化应激和肾脏损伤具有保护作用。