OXIDATION OF PHENYLALANINE TO OXALATE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 了解内源性草酸盐合成的途径和确定减少草酸盐产生的策略可能对原发性高尿酸患者有益。草酸是代谢的最终产物，主要在肝脏中合成。草酸盐的主要前体是乙醛酸盐，通常通过丙氨酸、乙醛酸转氨酶（AGT）转氨为甘氨酸，或通过乙醛酸还原酶（GR）还原为乙醇酸盐。在原发性高尿酸患者中，AGT或GR缺乏，草酸合成量增加，可引起肾脏病理。迄今为止确定的草酸盐的可能来源包括氨基酸：羟脯氨酸、甘氨酸、苯丙氨酸、酪氨酸和乙醇酸。我们之前使用13 C标记甘氨酸的研究（IRB#00003128）显示，<5%的尿草酸盐来自甘氨酸分解。苯丙氨酸是一种氨基酸，据报道在大鼠体内代谢后可产生草酸盐。我们最近观察到，培养的人肝细胞也可以将13 C-1苯丙氨酸转化为13 C-1草酸盐，这表明该途径可能在人类中起作用。苯丙氨酸在人体中的代谢主要发生在其转化为酪氨酸之后，但苯丙氨酸也可以脱氨基形成苯丙酮酸。这种酸可以形成不稳定的烯醇并分解成草酸盐。确定苯丙氨酸氧化对全身草酸盐合成的贡献可能有助于开发限制草酸盐合成的治疗策略。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Understanding the pathways of endogenous oxalate synthesis and identifying strategies that decrease oxalate production could be beneficial for individuals with primary hyperoxaluria. Oxalic acid is an end product of metabolism and is synthesized mainly in the liver. The main precursor of oxalate is glyoxylate and it is normally transaminated to glycine by alanine; glyoxylate aminotransferase (AGT) or reduced to glycolate by glyoxylate reductase (GR). In patients with primary hyperoxaluria either AGT or GR is deficient and the amount of oxalate synthesized increases which can cause renal pathology. The possible sources of oxalate identified to date include the amino acids: hydroxyproline, glycine, phenylalanine, tyrosine, and glycolate. Our previous study (IRB#00003128) using 13C-labeled glycine revealed that <5% of urinary oxalate is derived from glycine breakdown. Phenylalanine is an amino acid that has been reported to yield oxalate following its metabolism in rats. We have recently observed that human liver cells in culture can also convert 13 C-1 phenylalanine to 13 C-1 oxalate indicating that this pathway may function in humans. The metabolism of phenyalanine in humans occurs primarily following its conversion to tyrosine but phenylalanine can also be deaminated to form phenylpyruvate. This acid can form an unstable enol and break down to oxalate. Identifying the contribution of phenylalanine oxidation to total body oxalate synthesis could be helpful in developing therapuetic strategies that limit oxalate synthesis.