title: Post-Translational Incorporation of L-Phenylalanine into the C-Terminus of α-Tubulin as a Possible Cause of Neuronal Dysfunction.
abstract: α-Tubulin C-terminus undergoes post-translational, cyclic tyrosination/detyrosination, and L-Phenylalanine (Phe) can be incorporated in place of tyrosine. Using cultured mouse brain-derived cells and an antibody specific to Phe-tubulin, we showed that: (i) Phe incorporation into tubulin is reversible; (ii) such incorporation is not due to de novo synthesis; (iii) the proportion of modified tubulin is significant; (iv) Phe incorporation reduces cell proliferation without affecting cell viability; (v) the rate of neurite retraction declines as level of C-terminal Phe incorporation increases; (vi) this inhibitory effect of Phe on neurite retraction is blocked by the co-presence of tyrosine; (vii) microtubule dynamics is reduced when Phe-tubulin level in cells is high as a result of exogenous Phe addition and returns to normal values when Phe is removed; moreover, microtubule dynamics is also reduced when Phe-tubulin is expressed (plasmid transfection). It is known that Phe levels are greatly elevated in blood of phenylketonuria (PKU) patients. The molecular mechanism underlying the brain dysfunction characteristic of PKU is unknown. Beyond the differences between human and mouse cells, it is conceivable the possibility that Phe incorporation into tubulin is the first event (or among the initial events) in the molecular pathways leading to brain dysfunctions that characterize PKU.
authors.affiliation: Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC-CONICET, and Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA, Córdoba, Argentina.
authors.forename: Yanina
authors.initials: Y
authors.lastname: Ditamo
authors.affiliation: Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC-CONICET, and Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA, Córdoba, Argentina.
authors.forename: Yanela M
authors.initials: YM
authors.lastname: Dentesano
authors.affiliation: Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC-CONICET, and Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA, Córdoba, Argentina.
authors.forename: Silvia A
authors.initials: SA
authors.lastname: Purro
authors.affiliation: Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC-CONICET, and Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA, Córdoba, Argentina.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Arce
authors.affiliation: Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC-CONICET, and Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA, Córdoba, Argentina.
authors.forename: C Gastón
authors.initials: CG
authors.lastname: Bisig
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010649:Phenylalanine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010661:Phenylketonurias / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D014404:Tubulin; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D014443:Tyrosine; D010649:Phenylalanine