1 Department of Pediatrics, University of Colorado , School of Medicine, Aurora, Colorado.
2 Department of Pediatrics and Adolescent Medicine, Charles University-First Faculty of Medicine and General University Hospital in Prague , Prague, Czech Republic .
Antioxid Redox Signal. 2018 Feb 1;28(4):311-323. doi: 10.1089/ars.2017.7009. Epub 2017 Oct 11.
The transsulfuration pathway enzymes cystathionine beta-synthase (CBS) and cystathionine gamma-lyase are thought to be the major source of hydrogen sulfide (HS). In this study, we assessed the role of CBS in HS biogenesis.
We show that despite discouraging enzyme kinetics of alternative HS-producing reactions utilizing cysteine compared with the canonical condensation of serine and homocysteine, our simulations of substrate competitions at biologically relevant conditions suggest that cysteine is able to partially compete with serine on CBS, thus leading to generation of appreciable amounts of HS. The leading HS-producing reaction is condensation of cysteine with homocysteine, while cysteine desulfuration plays a dominant role when cysteine is more abundant than serine and homocysteine is limited. We found that the serine-to-cysteine ratio is the main determinant of CBS HS productivity. Abundance of cysteine over serine, for example, in plasma, allowed for up to 43% of CBS activity being responsible for HS production, while excess of serine typical for intracellular levels effectively limited such activity to less than 1.5%. CBS also produced lanthionine from serine and cysteine and a third of lanthionine coming from condensation of two cysteines contributed to the HS pool.
Our study characterizes the HS-producing potential of CBS under biologically relevant conditions and highlights the serine-to-cysteine ratio as the main determinant of HS production by CBS in vivo.
Our data clarify the function of CBS in HS biogenesis and the role of thioethers as surrogate HS markers. Antioxid. Redox Signal. 28, 311-323.
转硫途径中的酶胱硫醚β-合酶（CBS）和胱硫醚γ-裂解酶被认为是产生硫化氢（HS）的主要来源。在本研究中，我们评估了 CBS 在 HS 生物合成中的作用。
尽管利用半胱氨酸进行替代 HS 产生反应的酶动力学令人沮丧，与丝氨酸和同型半胱氨酸的经典缩合相比，但我们在生物学相关条件下对底物竞争的模拟表明，半胱氨酸能够在 CBS 上与丝氨酸部分竞争，从而产生相当数量的 HS。主要的 HS 产生反应是半胱氨酸与同型半胱氨酸的缩合，而当半胱氨酸的含量超过丝氨酸和同型半胱氨酸受到限制时，半胱氨酸的脱硫作用则起着主导作用。我们发现丝氨酸与半胱氨酸的比例是 CBS 产生 HS 能力的主要决定因素。例如，在血浆中，半胱氨酸相对于丝氨酸的丰度允许 CBS 活性的 43%负责 HS 的产生，而细胞内水平典型的丝氨酸过量有效地将这种活性限制在 1.5%以下。CBS 还从丝氨酸和半胱氨酸产生类硫氨酸，来自两个半胱氨酸缩合的三分之一的类硫氨酸有助于 HS 池的形成。
本研究在生物学相关条件下描述了 CBS 产生 HS 的潜力，并强调了丝氨酸与半胱氨酸的比例是 CBS 在体内产生 HS 的主要决定因素。
我们的数据阐明了 CBS 在 HS 生物合成中的功能以及硫醚作为 HS 替代标记物的作用。抗氧化还原信号。28,311-323。
