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

同型半胱氨酸(Hcy)和硫化氢(H_2S)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。同型半胱氨酸是一种中间氨基酸，通过必需氨基酸蛋氨酸转化为半胱氨酸而产生。同型半胱氨酸既可以再生为蛋氨酸，也可以代谢为半胱氨酸或硫化氢。胱硫醚β-合酶(CBS)是调节同型半胱氨酸代谢和H_2S生成的关键酶。CBS酶活性降低导致(1)Hcy升高和(2)血液中H2S水平降低。CBS酶存在于几个器官中，包括肾脏，它在调节硫、氨基酸和同型半胱氨酸代谢方面起着关键作用。人们早就知道，循环中同型半胱氨酸血症过多，这种情况称为高同型半胱氨酸血症，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。肾功能衰竭的常见原因之一是缺血再灌注损伤。缺血是一种低氧状态，流向组织的血流量减少或没有，再灌注是指恢复流向缺血组织的血流量。受影响的组织经历氧化应激，在这种情况下，细胞会受到活性氧的破坏。氧化应激发生在产生活性氧物种和抗氧化防御机制的解毒能力之间存在不平衡时。我们观察到，缺血再灌注导致CBS酶活性降低，导致Hcy在肾脏内积聚。同型半胱氨酸反过来又刺激肾脏中产生活性氧物种，导致氧化应激和细胞死亡。肾缺血再灌流后，肾组织中H_2S含量显著降低，与组织损伤程度呈负相关。在生理水平上，硫化氢起血管扩张剂和神经递质的作用。然而，硫化氢在肾脏中的生物学功能还不是很清楚。在拟议的研究中，我们的目标是确定(1)H_2S在肾脏中的作用(2)通过恢复CBS活性来调节H_2S的合成是否对缺血-再灌注引起的氧化应激和肾脏损伤具有保护作用。

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.