Nutritional Regulation of Cysteine Dioxygenase

半胱氨酸双加氧酶的营养调节

• 批准号: 7799019
• 负责人: MARTHA H STIPANUK
• 金额: $ 45.99万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7799019
• 关键词: Adverse effects; Affect; Anabolism; Animal Feed; Animals; Autoimmune Process; Catabolism; Chemistry; Clinical; Coenzyme A; Complement; Complex; Cysteamine; Cysteine; Cysteine Metabolism Pathway; Cysteine dioxygenase; Development; Diet; Diet Modification; Dietary Proteins; Dioxygenases; Disease; Early Diagnosis; Enzymes; Genes; Genetic Polymorphism; Glycosaminoglycans; Goals; Hepatic; Homeostasis; Hour; Human; Individual; Inorganic Sulfates; Knock-out; Knockout Mice; Life; Literature; Mediating; Metabolic; Metabolism; Modeling; Molecular; Mus; N-chlorotaurine; Names; Neurodegenerative Disorders; Nutritional; Organism; Oxygen; Phagocytes; Phenotype; Physiological; Population; Production; Proteins; Regulation; Role; Severities; Structure; Structure-Activity Relationship; Sulfhydryl Compounds; Sulfinic Acids; Sulfites; Sulfur Amino Acids; Taurine; Tissues; Unspecified or Sulfate Ion Sulfates; analog; base; cell type; disorder control; disorder prevention; genetic regulatory protein; hypotaurine; insight; loss of function mutation; mouse model; mutant; oxidation; prevent; public health relevance; response; sulfation

DESCRIPTION (provided by applicant): Cysteine catabolism is dependent upon two unique enzymes that are the only known mammalian thiol dioxygenases-enzymes adding molecular oxygen to a sulfhydryl group to form a sulfinic acid. These two unique enzymes are cysteine dioxygenase (CDO), encoded by CDO1, and cysteamine dioxygenase (ADO, 2-aminoethanethiol dioxygenase), which we recently showed to be encoded by human gene C10orf22. The clinical literature and, more recently, the study of CDO polymorphisms in disease and control populations, have shown a strong association of impaired metabolism of cysteine to sulfate and taurine and/or CDO loss-of-function mutations with a variety of autoimmune and neurodegenerative diseases. CDO is one of the most highly regulated metabolic enzymes responding to diet that is known, and this robust regulation of CDO activity suggests that cysteine homeostasis is very important to the living organism. Our long-term goals are integrate molecular and organismal studies (a) to further elucidate the structure-function relations in CDO and ADO to provide insights into thiol chemistry and regulation of these enzymes and (b) to further elucidate the roles of CDO and ADO in intermediary metabolism and regulation of physiological function in healthy individuals as well as the possible roles and contributions of CDO deficiency to autoimmune and/or neurodegenerative diseases. Our specific aims related are (1) to define the catalytic mechanism of CDO through structural and spectroscopic studies of complexes of wild type and mutant enzymes in complex with substrates, products and substrate analogs; (2) to crystallize and solve the structure of wild type ADO, and carry out studies to characterize its catalytic mechanism; (3) to characterize the phenotype of CDO-knockout or CDO-deficient mice, including those with tissue- specific CDO gene disruption; (4) to determine whether adverse effects of CDO gene disruption are affected by dietary manipulations (e.g., reduced by restricted cysteine, supplemental taurine, or supplemental sulfate, or amplified by diets containing excess sulfur amino acids, low taurine, or low sulfate); (5) to assess the functional contribution of CDO expressed in specific cell types or tissues to cysteine metabolism and regulation of cysteine levels; (6) to determine whether specific mechanisms that might contribute to the development or progression or severity of autoimmune and/or neurodegenerative disease -- including reduced taurine mediated antioxidation, reduced expression of the complement regulatory protein DAF, reduced capacity for sulfation of glycosaminoglycans, and increased production of H2S -- are altered in the CDO knockout mouse model; and (7) to assess the role of ADO in cysteamine metabolism and in the biosynthesis of hypotaurine/taurine by generating and studying an ADO knockout mouse model. PUBLIC HEALTH RELEVANCE: Cysteine homeostasis is very important to the living organism, and cysteine dioxygenase, the major enzyme involved in regulating body cysteine levels, can undergo ~300-fold changes in activity in response to changes in dietary protein content with these changes being accomplished within hours of the diet change. The clinical literature and the study of polymorphisms of the gene encoding cysteine dioxygenase (CDO1) in disease and control populations have shown a strong association of impaired metabolism of cysteine to sulfate and taurine and/or CDO1 loss-of-function mutations with a variety of autoimmune and neurodegenerative diseases. Further exploration of the structure and function of cysteine dioxygenase and use of a mouse knockout model to study the effects on loss-of-function mutations of CDO1 and their modification by diet will further our ability for prediction and early diagnosis of related disease states and for prevention of disease or alleviation of disease prevention by dietary modifications.

描述（由申请人提供）：半胱氨酸分解代谢依赖于两种独特的酶，这两种酶是唯一已知的哺乳动物硫醇双加氧酶——将分子氧添加到巯基上形成亚磺酸的酶。这两种独特的酶分别是由CDO1编码的半胱氨酸双加氧酶（CDO）和我们最近发现由人类基因C10orf22编码的半胱氨酸双加氧酶（ADO， 2-氨基乙硫醇双加氧酶）。临床文献以及最近对疾病和对照人群中CDO多态性的研究表明，半胱氨酸对硫酸盐和牛磺酸的代谢受损和/或CDO功能丧失突变与多种自身免疫性和神经退行性疾病密切相关。CDO是已知的对饮食反应最高度调节的代谢酶之一，这种对CDO活性的强大调节表明，半胱氨酸稳态对生物体非常重要。我们的长期目标是整合分子和组织研究(a)进一步阐明CDO和ADO的结构-功能关系，以提供对这些酶的硫醇化学和调节的见解；(b)进一步阐明CDO和ADO在健康个体的中间代谢和生理功能调节中的作用，以及CDO缺乏在自身免疫和/或神经退行性疾病中的可能作用和贡献。我们的具体目标是：(1)通过对野生型和突变型酶与底物、产物和底物类似物的配合物的结构和光谱研究来确定CDO的催化机制；(2)对野生型ADO的结构进行结晶求解，并对其催化机理进行表征研究；(3)描述CDO敲除或CDO缺陷小鼠的表型，包括组织特异性CDO基因破坏小鼠；(4)确定膳食操纵是否会影响CDO基因破坏的不良影响（例如，通过限制半胱氨酸、补充牛磺酸或补充硫酸盐来减少，或通过含有过量硫氨基酸、低牛磺酸或低硫酸盐的饮食来放大）；(5)评估特定细胞类型或组织中表达的CDO对半胱氨酸代谢和半胱氨酸水平调节的功能贡献；(6)确定可能导致自身免疫性和/或神经退行性疾病发生、进展或严重程度的特定机制——包括牛磺酸介导的抗氧化减少、补体调节蛋白DAF的表达减少、糖胺聚糖硫酸化能力降低和H2S的产生增加——在CDO敲除小鼠模型中是否发生改变；(7)通过建立和研究ADO敲除小鼠模型，评估ADO在半胱胺代谢和次牛磺酸/牛磺酸生物合成中的作用。公共卫生相关性：半胱氨酸体内平衡对生物体非常重要，半胱氨酸双加氧酶是调节体内半胱氨酸水平的主要酶，随着饮食蛋白质含量的变化，其活性会发生约300倍的变化，而这些变化在饮食改变后数小时内就会完成。临床文献和对疾病和对照人群中编码半胱氨酸双加氧酶（CDO1）基因多态性的研究表明，半胱氨酸对硫酸盐和牛磺酸的代谢受损和/或CDO1功能丧失突变与多种自身免疫性和神经退行性疾病密切相关。进一步探索半胱氨酸双加氧酶的结构和功能，并使用小鼠敲除模型来研究CDO1功能缺失突变及其饮食修饰的影响，将进一步提高我们预测和早期诊断相关疾病状态的能力，以及通过饮食修饰预防疾病或减轻疾病预防的能力。