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Mol Genet Metab. 2013;110 Suppl:S71-8. doi: 10.1016/j.ymgme.2013.08.004. Epub 2013 Aug 15.

Characterization of 2-(methylamino)alkanoic acid capacity to restrict blood-brain phenylalanine transport in Pah enu2 mice: preliminary findings.

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Section of Clinical Pharmacology, College of Pharmacy, Washington State University, Spokane, WA, USA.



Our laboratory seeks a pharmacotherapeutic intervention for PKU that utilizes non-physiological amino acids (NPAAs) to block the accumulation of phenylalanine (Phe) in the brain. In previous studies (Vogel et al. 2013), methylation of the amino group of 2-aminoisobutyrate (AIB) provided an enhanced degree of selectivity for Phe restriction into the brain of Pah(enu2) mice in comparison to unmethylated AIB, leading to the hypothesis that 2-(methylamino)alkanoic acid analogs of AIB might represent targeted inhibitors of Phe accretion into the brain.


Pah(enu2) and control mice were intraperitoneally administered (500-750 mg/kg body weight, once daily; standard 19% protein diet) AIB, methyl AIB (MAIB), isovaline, and two MAIB analogs, 2-methyl-2-(methylamino)butanoic (MeVal) and 3-methyl-2-(methylamino)pentanoic (MePent) acids for one week, followed by brain and blood isolation for amino acid analyses using UPLC.


In the brain, AIB significantly reduced Phe accretion in Pah(enu2) mice, while MeVal significantly improved glutamine and aspartic acids. Four of five test compounds improved brain threonine and arginine levels. AIB, MAIB and IsoVal significantly reduced blood Phe, with no effect of any drug intervention on other sera amino acids.


Further evaluation of AIB and the 2-(methylamino)alkanoic acids as inhibitors of brain Phe accumulation in Pah(enu2) mice is warranted, with more detailed evaluations of route of administration, combinatorial intervention, and detailed toxicity studies.


2-(Methylamino)alkanoic acids; 2-aminoisobutyrate (also 2-methyl-2-aminopropionic acid); 3-methyl-2-(methylamino)pentanoic acid; A transporter; AIB; ASC transporter; Ala; Arg; Asp; BBB; BCAA; DOL; GABA; Gln; Glu; Gly; His; Ile; IsoVal; LAT 1-4; LNAA; LNAA transport system, system L transporter; Large neutral amino acid transporter (LAT-1); Large neutral amino acids (LNAA); Leu; MAIB; MePent; MeVal; Met; NPAA; Non-physiological amino acids (NPAA); PBS; PKU; Pah(enu2) mice; Phe; Phenylketonuria (PKU); Thr; Trp; Tyr; Val; X transporter; Y transporter; alanine; arginine; aspartic acid; blood–brain barrier; branched chain amino acids (Leu, Ile, Val); day of life; gamma-aminobutyric acid; glutamic acid; glutamine; glycine; histidine; i.p; intraperitoneal drug administration; isoleucine; isovaline (also 2-methyl-2-aminobutanoic acid); large neutral amino acids; leucine; methionine; methylaminoisobutyrate (also 2-methyl-2-(methylamino)propionic acid); methylvaline (also 3-methyl-2-(methylamino)butanoic acid); murine model of PKU developed with ethylnitrosourea mutagenesis; non-physiological amino acid; phenylalanine; phenylketonuria; phosphate buffered saline; system A (alanine) transport system (small neutral amino acids); system ASC (alanine-serine-cysteine) transport system; system X (acidic amino acid) transporter; system Y (basic amino acid) transporter; threonine; tryptophan; tyrosine; valine

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