Fluorination at the 4 position alters the substrate behavior of L-glutamine and L-glutamate: Implications for positron emission tomography of neoplasias.
Fluorination at the 4 position alters the substrate behavior of L-glutamine and L-glutamate: Implications for positron emission tomography of neoplasias.
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DOI：
10.1016/j.jfluchem.2016.10.008
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发表时间：
2016-12
影响因子：
1.9
通讯作者：
Cooper AJL
中科院分区：
文献类型：
--
作者：
Jeitner TM;Kristoferson E;Azcona JA;Pinto JT;Stalnecker C;Erickson JW;Kung HF;Li J;Ploessl K;Cooper AJL
先前开发了两种 4-氟-L-谷氨酰胺非对映异构体 [(2S,4R)-4-FGln、(2S,4S)-4-FGln] 用于正电子发射断层扫描。 [ 18 F](2S,4R)-4-FGln 比[ 18 F](2S,4S)-4-FGln 对两种肿瘤细胞类型的标记摄取更大。在目前的工作中，我们研究了 4-FGln 的两种非对映异构体、4-氟谷氨酸 (4-FGlu) 的两种非对映异构体（4-FGln 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)]。发现两种 4-FGlu 非对映异构体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-谷氨酸是中等至良好的底物。此外，丙氨酸转氨酶可催化两种 4-FGlu 非对映异构体发生不寻常的 γ-消除反应。两种 4-FGlu 非对映异构体均被证明是弱底物，但却是谷氨酰胺合成酶的强抑制剂。与谷氨酰胺转氨酶 L 和 α-氨基己二酸转氨酶的 L-谷氨酰胺相比，两种 4-FGln 非对映异构体都被证明是较差的底物。然而，(2S,4R)-4-FGln 被发现是谷氨酰胺转氨酶 K 的较差底物，而 (2S,4S)-4-FGln 被证明是极好的底物。相比之下，FP-Gln 被发现是所有检查的酶的较差底物。显然，L-谷氨酰胺/L-谷氨酸中4位H被F取代对酶催化反应具有中度至深度的影响。目前的结果：1)表明4-FGln和4-FGlu非对映异构体可用于研究谷氨酸和谷氨酰胺利用酶的活性位点拓扑结构； 2) 提供一个框架来理解18F标记的(2S,4R)-4-FGln、(2S,4S)-4-FGln、(2S,4R)-4-FGlu或(2S,4S)-4-FGlu在肿瘤中可能的代谢转化；和3)显示[ 18 F]FP-Gln在体内的代谢活性可能比[ 18 F] 4-FGln非对映异构体低得多。 4-FGln 和 4-FGln 的 2S,4S- 和 2S,4R 非对映异构体的代谢 实线箭头表示 4-FGln 和 4F-Glu 的 2S,4S- 和 2S,4R 非对映异构体的拟议代谢途径，而虚线箭头表示不太受欢迎的途径。
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. Metabolism of the 2S,4S- and 2S,4R diastereoisomers of 4-FGln and 4-FGln The solid arrows indicate the proposed metabolic pathways for the 2S,4S- and 2S,4R diastereoisomers of 4-FGln and 4F–Glu, while the broken arrows indicate the less favored pathways.