Hutson S M, Berkich D, Drown P, Xu B, Aschner M, LaNoue K F
Department of Biochemistry, Wake Forest University Medical School, Winston-Salem, North Carolina 27157, USA.
J Neurochem. 1998 Aug;71(2):863-74. doi: 10.1046/j.1471-4159.1998.71020863.x.
Because it is well known that excess branched-chain amino acids (BCAAs) have a profound influence on neurological function, studies were conducted to determine the impact of BCAAs on neuronal and astrocytic metabolism and on trafficking between neurons and astrocytes. The first step in the metabolism of BCAAs is transamination with alpha-ketoglutarate to form the branched-chain alpha-keto acids (BCKAs). The brain is unique in that it expresses two separate branched-chain aminotransferase (BCAT) isoenzymes. One is the common peripheral form [mitochondrial (BCATm)], and the other [cytosolic (BCATc)] is unique to cerebral tissue, placenta, and ovaries. Therefore, attempts were made to define the isoenzymes' spatial distribution and whether they might play separate metabolic roles. Studies were conducted on primary rat brain cell cultures enriched in either astroglia or neurons. The data show that over time BCATm becomes the predominant isoenzyme in astrocyte cultures and that BCATc is prominent in early neuronal cultures. The data also show that gabapentin, a structural analogue of leucine with anticonvulsant properties, is a competitive inhibitor of BCATc but that it does not inhibit BCATm. Metabolic studies indicated that BCAAs promote the efflux of glutamine from astrocytes and that gabapentin can replace leucine as an exchange substrate. Studying astrocyte-enriched cultures in the presence of [U-14C]glutamate we found that BCKAs, but not BCAAs, stimulate glutamate transamination to alpha-ketoglutarate and thus irreversible decarboxylation of glutamate to pyruvate and lactate, thereby promoting glutamate oxidative breakdown. Oxidation of glutamate appeared to be largely dependent on the presence of an alpha-keto acid acceptor for transamination in astrocyte cultures and independent of astrocytic glutamate dehydrogenase activity. The data are discussed in terms of a putative BCAA/BCKA shuttle, where BCATs and BCAAs provide the amino group for glutamate synthesis from alpha-ketoglutarate via BCATm in astrocytes and thereby promote glutamine transfer to neurons, whereas BCATc reaminates the amino acids in neurons for another cycle.
由于众所周知过量的支链氨基酸（BCAAs）对神经功能有深远影响，因此开展了多项研究以确定BCAAs对神经元和星形胶质细胞代谢以及神经元与星形胶质细胞之间物质转运的影响。BCAAs代谢的第一步是与α-酮戊二酸进行转氨反应，形成支链α-酮酸（BCKAs）。大脑的独特之处在于它表达两种不同的支链氨基转移酶（BCAT）同工酶。一种是常见的外周形式[线粒体（BCATm）]，另一种[胞质（BCATc）]则是脑组织、胎盘和卵巢所特有的。因此，研究人员试图确定这些同工酶的空间分布以及它们是否可能发挥不同的代谢作用。研究人员对富含星形胶质细胞或神经元的原代大鼠脑细胞培养物进行了研究。数据表明，随着时间的推移，BCATm成为星形胶质细胞培养物中的主要同工酶，而BCATc在早期神经元培养物中占主导地位。数据还表明，加巴喷丁是亮氨酸的结构类似物，具有抗惊厥特性，是BCATc的竞争性抑制剂，但不抑制BCATm。代谢研究表明，BCAAs促进谷氨酰胺从星形胶质细胞中流出，并且加巴喷丁可以替代亮氨酸作为交换底物。在存在[U-14C]谷氨酸的情况下研究富含星形胶质细胞的培养物时，我们发现BCKAs而非BCAAs刺激谷氨酸转氨生成α-酮戊二酸，从而使谷氨酸不可逆地脱羧生成丙酮酸和乳酸，进而促进谷氨酸的氧化分解。谷氨酸的氧化似乎在很大程度上取决于星形胶质细胞培养物中转氨反应中α-酮酸受体的存在，并且与星形胶质细胞谷氨酸脱氢酶活性无关。我们从一个假定的BCAA/BCKA穿梭机制来讨论这些数据，其中BCATs和BCAAs通过星形胶质细胞中的BCATm为从α-酮戊二酸合成谷氨酸提供氨基，从而促进谷氨酰胺向神经元的转运，而BCATc在神经元中使氨基酸重新氨基化以进行另一个循环。
