Two 4-fluoro-L-glutamine diastereoisomers [(2S,4R)-4-FGln, (2S,4S)-4-FGln] were previously developed for positron emission tomography. Label uptake into two tumor cell types was greater with [18F](2S,4R)-4-FGln than with [18F](2S,4S)-4-FGln. In the present work we investigated the enzymology of two diastereoisomers of 4-FGln, two diastereoisomers of 4-fluoroglutamate (4-FGlu) (potential metabolites of the 4-FGln diastereoisomers) and another fluoro-derivative of L-glutamine [(2S,4S)-4-(3-fluoropropyl)glutamine (FP-Gln)]. The two 4-FGlu diastereoisomers were found to be moderate-to-good substrates relative to L-glutamate of glutamate dehydrogenase, aspartate aminotransferase and alanine aminotransferase. Additionally, alanine aminotransferase was shown to catalyze an unusual γ-elimination reaction with both 4-FGlu diastereoisomers. Both 4-FGlu diastereoisomers were shown to be poor substrates, but strong inhibitors of glutamine synthetase. Both 4-FGln diastereoisomers were shown to be poor substrates compared to L-glutamine of glutamine transaminase L and α-aminoadipate aminotransferase. However, (2S,4R)-4-FGln was found to be a poor substrate of glutamine transaminase K, whereas (2S,4S)-4-FGln was shown to be an excellent substrate. By contrast, FP-Gln was found to be a poor substrate of all enzymes examined. Evidently, substitution of H in position 4 by F in L-glutamine/L-glutamate has moderate-to-profound effects on enzyme-catalyzed reactions. The present results: 1) show that 4-FGln and 4-FGlu diastereoisomers may be useful for studying active site topology of glutamate- and glutamine-utilizing enzymes; 2) provide a framework for understanding possible metabolic transformations in tumors of 18F-labeled (2S,4R)-4-FGln, (2S,4S)-4-FGln, (2S,4R)-4-FGlu or (2S,4S)-4-FGlu; and 3) show that [18F]FP-Gln is likely to be much less metabolically active in vivo than are the [18F]4-FGln diastereoisomers.

中文翻译：

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在4位上的氟化改变了L-谷氨酰胺和L-谷氨酸的底物行为：对肿瘤形成的正电子发射断层扫描的影响。

先前已开发出两种用于正电子发射断层扫描的4-氟-L-谷氨酰胺非对映异构体[（2S，4R）-4-FGln，（2S，4S）-4-FGln]。[18F]（2S，4R）-4-FGln标记物对两种肿瘤细胞的摄取大于[18F]（2S，4S）-4-FGln标记物摄取。在本研究中，我们研究了4-FGln的两种非对映异构体，4-氟谷氨酸的两种非对映异构体（4-FGlu）（4-FGln的非对映异构体的潜在代谢物）和L-谷氨酰胺的另一种氟衍生物[（2S， 4S）-4-（3-氟丙基）谷氨酰胺（FP-Gln）]。相对于谷氨酸脱氢酶，天冬氨酸转氨酶和丙氨酸转氨酶的L-谷氨酸，发现两种4-FGlu非对映异构体是中等至良好的底物。另外，显示丙氨酸氨基转移酶与两种4-FGlu非对映异构体一起催化异常的γ消除反应。两种4-FGlu非对映异构体均显示为较差的底物，但是谷氨酰胺合成酶的强抑制剂。与谷氨酰胺转氨酶L和α-氨基己二酸氨基转移酶的L-谷氨酰胺相比，两种4-FGln非对映异构体均显示为差的底物。但是，发现（2S，4R）-4-FGln是谷氨酰胺转氨酶K的较差底物，而（2S，4S）-4-FGln被认为是极好的底物。相比之下，发现FP-Gln是所有检测酶的不良底物。显然，L-谷氨酰胺/ L-谷氨酸中的F被4位的H取代对酶催化的反应具有中等至深远的影响。目前的结果：1）表明4-FGln和4-FGlu非对映异构体可能对研究谷氨酸和谷氨酰胺利用酶的活性位点拓扑结构有用；2）为理解18F标记的（2S，4R）-4-FGln，（2S，4S）-4-FGln，（2S，4R）-4-FGlu或（2S，4S）的肿瘤中可能的代谢转化提供了框架）-4-FGlu；和3）表明[18F] FP-Gln在体内的代谢活性可能比[18F] 4-FGln非对映异构体低。