金属蛋白酶 DUBs
中文名称
通路描述
JAB1/MPN +/MOV34 (JAMM) 结构域金属蛋白酶在多聚泛素连接点附近或在其处切割异肽键。PSMD14 (RPN11)、STAMBP (AMSH)、STAMBPL1 (AMSH-LP) 和 BRCC3 (BRCC36) 对 K63 多泛素连接具有高度特异性，这可能是一种普遍特征。另外两个多亚基复合物在 Reactome 中另有描述，包含 JAMM DUBs。蛋白酶体 19S 盖子复合物包括 PSMD14，这是一种内肽酶，在泛素链被蛋白酶体降解时从底物上切割多聚泛素链。COP9-Signalosome 包含 COPS5 (CSN5)，它去泛素化 Nedd8 修饰物，调节 SCF E3 连接酶 (Cope et al. 2002) 的活性。JAMM DUB 催化需要水分子在 Zn2+ 和保守谷氨酸的协助下对异肽键的羰基碳进行亲核攻击。随后形成带负电荷的四面体过渡态，JAMM 结构域附近保守的 Ser/Thr 稳定氧阴离子。四面体中间体随后分解，Glu 作为一般碱将质子给予离去侧链赖氨酸 (Ambroggio et al. 2004)。
英文描述
Mitochondrial Uncoupling The protonmotive force across the inner mitochondrial membrane built up by respiratory electron transport does not go entirely into ATP production. Transport proteins of the SLC25 type utilize the gradient to symport small molecules with protons into the matrix, simultaneously generating heat ("thermogenesis"). UCP1 and AAC1 have been shown to import protons exclusively and are responsible for most heat generated in brown fat and other tissue, respectively (reviewed in Bertholet & Kirichok, 2022).
Uncoupling proteins (UCPs) are members of the mitochondrial transport carrier family. The crystal structure of one member of the family, the adenine nucleotide translocase, is known, and UCPs can be successfully folded into this structure to indicate their probable 3D arrangement (Pebay-Peyroula et al. 2003, Kunji 2004, Esteves & Brand 2005).
The most studied member of the family, UCP1, catalyzes adaptive thermogenesis (i.e., heat generation) in mammalian brown adipose tissue. It does so by promoting a leak of protons through the mitochondrial inner membrane, which uncouples ATP production from substrate oxidation, leading to fast oxygen consumption and ultimately to heat production. The thermogenic activity of UCP1 in brown adipose tissue plays an important role when the organism needs extra heat, e.g., during cold weather conditions (for small rodents), the cold stress of birth, or arousal from hibernation. UCP1 homologs have been found in lower vertebrates such as fish, where their role is unclear (Cannon & Nedergaard 2004, Jastroch et al. 2005).
The proton conductance of UCP1 in brown adipose tissue is tightly controlled. It is strongly inhibited by physiological concentrations of purine nucleotides. This inhibition is overcome by fatty acids released from intracellular triacylglycerol stores following adrenergic activation in response to cold or overfeeding. Other activators include superoxide, retinoic acid, the retinoid 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphtalenyl)-1-propenyl]benzoic acid (TTNPB) and reactive alkenals, such as hydroxynonenal.
There is strong evidence that the regulated uncoupling caused by these proteins attenuates mitochondrial reactive oxygen species production, protects against cellular damage, and (in beta-cells) diminishes insulin secretion. There are also untested suggestions that their transport of fatty acids may be physiologically important (Brand & Esteves 2005, Esteves & Brand 2005, Krauss et al. 2005).
Several models have been proposed for the molecular mechanism by which fatty acids lead to increased proton conductance by UCP1 in brown adipose tissue mitochondria and presumably by the other UCPs. We have depicted the most likely model, the "fatty acid cycling" model, in this pathway .
Studies of mouse models and cultured human cells have suggested that oleoyl-phenylalanine, synthesized by extracellular PM20D1, may play a role in uncoupling independent of the action of UCPs (Long et al., 2016). Its synthesis and hydrolysis are annotated here.
Uncoupling proteins (UCPs) are members of the mitochondrial transport carrier family. The crystal structure of one member of the family, the adenine nucleotide translocase, is known, and UCPs can be successfully folded into this structure to indicate their probable 3D arrangement (Pebay-Peyroula et al. 2003, Kunji 2004, Esteves & Brand 2005).
The most studied member of the family, UCP1, catalyzes adaptive thermogenesis (i.e., heat generation) in mammalian brown adipose tissue. It does so by promoting a leak of protons through the mitochondrial inner membrane, which uncouples ATP production from substrate oxidation, leading to fast oxygen consumption and ultimately to heat production. The thermogenic activity of UCP1 in brown adipose tissue plays an important role when the organism needs extra heat, e.g., during cold weather conditions (for small rodents), the cold stress of birth, or arousal from hibernation. UCP1 homologs have been found in lower vertebrates such as fish, where their role is unclear (Cannon & Nedergaard 2004, Jastroch et al. 2005).
The proton conductance of UCP1 in brown adipose tissue is tightly controlled. It is strongly inhibited by physiological concentrations of purine nucleotides. This inhibition is overcome by fatty acids released from intracellular triacylglycerol stores following adrenergic activation in response to cold or overfeeding. Other activators include superoxide, retinoic acid, the retinoid 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphtalenyl)-1-propenyl]benzoic acid (TTNPB) and reactive alkenals, such as hydroxynonenal.
There is strong evidence that the regulated uncoupling caused by these proteins attenuates mitochondrial reactive oxygen species production, protects against cellular damage, and (in beta-cells) diminishes insulin secretion. There are also untested suggestions that their transport of fatty acids may be physiologically important (Brand & Esteves 2005, Esteves & Brand 2005, Krauss et al. 2005).
Several models have been proposed for the molecular mechanism by which fatty acids lead to increased proton conductance by UCP1 in brown adipose tissue mitochondria and presumably by the other UCPs. We have depicted the most likely model, the "fatty acid cycling" model, in this pathway .
Studies of mouse models and cultured human cells have suggested that oleoyl-phenylalanine, synthesized by extracellular PM20D1, may play a role in uncoupling independent of the action of UCPs (Long et al., 2016). Its synthesis and hydrolysis are annotated here.
所含基因
2 个基因