H2S Biogenesis by Human Cystathionine γ-Lyase Leads to the Novel Sulfur Metabolites Lanthionine and Homolanthionine and Is Responsive to the Grade of Hyperhomocysteinemia
H2S Biogenesis by Human Cystathionine γ-Lyase Leads to the Novel Sulfur Metabolites Lanthionine and Homolanthionine and Is Responsive to the Grade of Hyperhomocysteinemia
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DOI：
10.1074/jbc.m808026200
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发表时间：
2009-04-24
影响因子：
4.8
通讯作者：
Banerjee, Ruma
中科院分区：
文献类型：
--
作者：
Chiku, Taurai;Padovani, Dominique;Banerjee, Ruma
尽管人们日益认识到硫化氢（H₂S）作为一种参与血管和神经系统功能的生物信号分子的重要性，但其生物合成和调节机制却鲜为人知。人们普遍认为，半胱氨酸的脱硫氢作用是哺乳动物体内H₂S的主要来源，并且由转硫途径的酶——胱硫醚β - 合成酶和胱硫醚γ - 裂解酶（CSE）催化。在本研究中，我们证明人类CSE的多种反应特性可导致从半胱氨酸和同型半胱氨酸生成H₂S。γ - 取代反应使两个同型半胱氨酸分子缩合，产生H₂S和一种新型生物标志物——高羊毛氨酸，据报道同型半胱氨酸尿症患者的尿液中存在这种物质；而β - 取代反应使两个半胱氨酸分子缩合，生成羊毛硫氨酸。在生理相关的半胱氨酸和同型半胱氨酸浓度下进行的动力学模拟显示，半胱氨酸的α,β - 消除反应约占H₂S生成量的70%。然而，随着同型半胱氨酸血症的严重程度增加，源自同型半胱氨酸的H₂S的相对重要性逐渐增加，在同型半胱氨酸严重升高（200 μM）的条件下，预计同型半胱氨酸的α,β - 消除反应和γ - 取代反应共同约占CSE生成H₂S量的90%。同型半胱氨酸血症中过多的H₂S产生可能与相关的心血管病理有关。
Although there is a growing recognition of the significance of hydrogen sulfide (H2S) as a biological signaling molecule involved in vascular and nervous system functions, its biogenesis and regulation are poorly understood. It is widely assumed that desulfhydration of cysteine is the major source of H2S in mammals and is catalyzed by the transsulfuration pathway enzymes, cystathionine beta-synthase and cystathionine gamma-lyase (CSE). In this study, we demonstrate that the profligacy of human CSE results in a variety of reactions that generate H2S from cysteine and homocysteine. The gamma-replacement reaction, which condenses two molecules of homocysteine, yields H2S and a novel biomarker, homolanthionine, which has been reported in urine of homocystinuric patients, whereas a beta-replacement reaction, which condenses two molecules of cysteine, generates lanthionine. Kinetic simulations at physiologically relevant concentrations of cysteine and homocysteine, reveal that the alpha,beta-elimination of cysteine accounts for similar to 70% of H2S generation. However, the relative importance of homocysteine-derived H2S increases progressively with the grade of hyperhomocysteinemia, and under conditions of severely elevated homocysteine (200 mu M), the alpha,beta-elimination and gamma-replacement reactions of homocysteine together are predicted to account for similar to 90% of H2S generation by CSE. Excessive H2S production in hyperhomocysteinemia may contribute to the associated cardiovascular pathology.