Butterfield D Allan, Lange Miranda L Bader
Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506-0055, USA.
J Neurochem. 2009 Nov;111(4):915-33. doi: 10.1111/j.1471-4159.2009.06397.x. Epub 2009 Sep 23.
Enolase enzymes are abundantly expressed, cytosolic carbon-oxygen lyases known for their role in glucose metabolism. Recently, enolase has been shown to possess a variety of different regulatory functions, beyond glycolysis and gluconeogenesis, associated with hypoxia, ischemia, and Alzheimer's disease (AD). AD is an age-associated neurodegenerative disorder characterized pathologically by elevated oxidative stress and subsequent damage to proteins, lipids, and nucleic acids, appearance of neurofibrillary tangles and senile plaques, and loss of synapse and neuronal cells. It is unclear if development of a hypometabolic environment is a consequence of or contributes to AD pathology, as there is not only a significant decline in brain glucose levels in AD, but also there is an increase in proteomics identified oxidatively modified glycolytic enzymes that are rendered inactive, including enolase. Previously, our laboratory identified alpha-enolase as one the most frequently up-regulated and oxidatively modified proteins in amnestic mild cognitive impairment (MCI), early-onset AD, and AD. However, the glycolytic conversion of 2-phosphoglycerate to phosphoenolpyruvate catalyzed by enolase does not directly produce ATP or NADH; therefore it is surprising that, among all glycolytic enzymes, alpha-enolase was one of only two glycolytic enzymes consistently up-regulated from MCI to AD. These findings suggest enolase is involved with more than glucose metabolism in AD brain, but may possess other functions, normally necessary to preserve brain function. This review examines potential altered function(s) of brain enolase in MCI, early-onset AD, and AD, alterations that may contribute to the biochemical, pathological, clinical characteristics, and progression of this dementing disorder.
烯醇化酶是一种大量表达的胞质碳氧裂解酶，因其在葡萄糖代谢中的作用而闻名。最近研究表明，烯醇化酶除了在糖酵解和糖异生中发挥作用外，还具有多种与缺氧、缺血和阿尔茨海默病（AD）相关的不同调节功能。AD是一种与年龄相关的神经退行性疾病，其病理特征为氧化应激升高以及随后蛋白质、脂质和核酸受损，出现神经原纤维缠结和老年斑，以及突触和神经元细胞丢失。目前尚不清楚低代谢环境的形成是AD病理的结果还是促成因素，因为AD患者不仅脑葡萄糖水平显著下降，而且蛋白质组学鉴定出的氧化修饰的糖酵解酶（包括烯醇化酶）增加，这些酶失去了活性。此前，我们实验室发现α-烯醇化酶是遗忘型轻度认知障碍（MCI）、早发性AD和AD中上调最频繁且被氧化修饰的蛋白质之一。然而，烯醇化酶催化的2-磷酸甘油酸向磷酸烯醇丙酮酸的糖酵解转化并不直接产生ATP或NADH；因此，在所有糖酵解酶中，α-烯醇化酶是从MCI到AD持续上调的仅有的两种糖酵解酶之一，这一点令人惊讶。这些发现表明烯醇化酶在AD脑中涉及的不仅仅是葡萄糖代谢，可能还具有其他功能，这些功能通常对维持脑功能是必需的。本综述探讨了MCI、早发性AD和AD中脑烯醇化酶潜在的功能改变，这些改变可能有助于这种痴呆症的生化、病理、临床特征及病情进展。
