Clinical and mutational investigations of tyrosinemia type II in Northern Tunisia: Identification and structural characterization of two novel TAT mutations

Charfeddine, Chérine; Monastiri, K.; Mokni, M.; Laadjimi, A.; Kaabachi, N.; Perin, O.; Nilges, Michaël; Kassar, Selma; Keirallah, M.; Guédiche, M.N.; Kamoun, Mohamed Ridha; Tebib, Néji; Dridi, M. F. Ben; Boubaker, Samir; Osman, A. Ben; Abdelhak, Sonia

doi:10.1016/j.ymgme.2006.02.006

Cited by 24 publications

(15 citation statements)

References 25 publications

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“…In tyrosinemia type II, tyrosine accumulates in blood, eventually causing lesions in the patients (al-Hemidan and al-Hazzaa, 1995). In humans, more than 15 mutations have been identified in the patients of tyrosinemia type II in Italy, France, USA and the UK (Natt et al, 1992; Endo, 1998; Charfeddine et al, 2006; Maydan et al, 2006; Minami-Hori et al, 2006; Meissner et al, 2008; Pasternack et al, 2009). Tyrosinemia type II is often associated with consanguinity.…”

Section: Introductionmentioning

confidence: 99%

Tyrosine aminotransferase: biochemical and structural properties and molecular dynamics simulations

et al. 2010

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Tyrosine aminotransferase (TAT) catalyzes the transamination of tyrosine and other aromatic amino acids. The enzyme is thought to play a role in tyrosinemia type II, hepatitis and hepatic carcinoma recovery. The objective of this study is to investigate its biochemical and structural characteristics and substrate specificity in order to provide insight regarding its involvement in these diseases. Mouse TAT (mTAT) was cloned from a mouse cDNA library, and its recombinant protein was produced using Escherichia coli cells and purified using various chromatographic techniques. The recombinant mTAT is able to catalyze the transamination of tyrosine using α-ketoglutaric acid as an amino group acceptor at neutral pH. The enzyme also can use glutamate and phenylalanine as amino group donors and p-hydroxy-phenylpyruvate, phenylpyruvate and alpha-ketocaproic acid as amino group acceptors. Through macromolecular crystallography we have determined the mTAT crystal structure at 2.9 Å resolution. The crystal structure revealed the interaction between the pyridoxal-5′-phosphate cofactor and the enzyme, as well as the formation of a disulphide bond. The detection of disulphide bond provides some rational explanation regarding previously observed TAT inactivation under oxidative conditions and reactivation of the inactive TAT in the presence of a reducing agent. Molecular dynamics simulations using the crystal structures of Trypanosoma cruzi TAT and human TAT provided further insight regarding the substrate-enzyme interactions and substrate specificity. The biochemical and structural properties of TAT and the binding of its cofactor and the substrate may help in elucidation of the mechanism of TAT inhibition and activation.

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Section: Introductionmentioning

confidence: 99%

Tyrosine aminotransferase: biochemical and structural properties and molecular dynamics simulations

et al. 2010

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“…To examine potential influence of these amino acid changes on the function of TAT in Old World fruit bats, we collected and mapped reported human amino acid mutations that cause tyrosinemia type II (R119W, C151Y, L201R, P220S, L273P, G362V and R443Q/W) [9], [10], [13], [14], [15] into the sequence alignment (Figure S2). None of 21 amino acid changes in the Old World fruit bats occurred at any of these amino acid positions (Figure S2), suggesting that additional amino acid positions affect the enzymatic function of TAT.…”

Section: Discussionmentioning

confidence: 99%

“…Deficiency of TAT, which is caused by genetic mutations in the Tat gene, in humans leads to tyrosinemia type II syndrome characterized by elevated blood tyrosine levels, mental retardation, etc [8]. To date, more than 15 distinct mutations [8], [9], [10], [11], [12], [13], [14], [15] have been identified in humans that cause tyrosinemia type II.…”

Section: Introductionmentioning

confidence: 99%

Relaxed Evolution in the Tyrosine Aminotransferase Gene Tat in Old World Fruit Bats (Chiroptera: Pteropodidae)

et al. 2014

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Frugivorous and nectarivorous bats fuel their metabolism mostly by using carbohydrates and allocate the restricted amounts of ingested proteins mainly for anabolic protein syntheses rather than for catabolic energy production. Thus, it is possible that genes involved in protein (amino acid) catabolism may have undergone relaxed evolution in these fruit- and nectar-eating bats. The tyrosine aminotransferase (TAT, encoded by the Tat gene) is the rate-limiting enzyme in the tyrosine catabolic pathway. To test whether the Tat gene has undergone relaxed evolution in the fruit- and nectar-eating bats, we obtained the Tat coding region from 20 bat species including four Old World fruit bats (Pteropodidae) and two New World fruit bats (Phyllostomidae). Phylogenetic reconstructions revealed a gene tree in which all echolocating bats (including the New World fruit bats) formed a monophyletic group. The phylogenetic conflict appears to stem from accelerated TAT protein sequence evolution in the Old World fruit bats. Our molecular evolutionary analyses confirmed a change in the selection pressure acting on Tat, which was likely caused by a relaxation of the evolutionary constraints on the Tat gene in the Old World fruit bats. Hepatic TAT activity assays showed that TAT activities in species of the Old World fruit bats are significantly lower than those of insectivorous bats and omnivorous mice, which was not caused by a change in TAT protein levels in the liver. Our study provides unambiguous evidence that the Tat gene has undergone relaxed evolution in the Old World fruit bats in response to changes in their metabolism due to the evolution of their special diet.

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“…PPK manifests during the first year of life but may also develop in adolescence and affects fingertips and thenar and hypothenar eminences on the palms and weight‐bearing areas on the soles. The degree of intellectual disability may relate to serum tyrosine levels and ranges from borderline intelligence decrease to a severe mental impairment with microcephaly …”

Section: Syndromic Palmoplantar Keratodermasmentioning

confidence: 99%

“…The degree of intellectual disability may relate to serum tyrosine levels and ranges from borderline intelligence decrease to a severe mental impairment with microcephaly. 78 Palmoplantar keratoderma, severe dermatitis, multiple allergies and metabolic wasting (SAM syndrome), due to DSG1 (Table 6). It is mostly due to biallelic mutations of DSG1 (Table S1), encoding the desmosomal protein desmoglein 1.…”

Section: Palmoplantar Keratodermas With Other Systemic Signsmentioning

confidence: 99%

Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas – Diagnostic algorithm and principles of therapy

Guerra

Castori²,

Didona

et al. 2018

Acad Dermatol Venereol

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Hereditary palmoplantar keratodermas (PPKs) comprise a large and heterogeneous group of disorders characterized by persistent thickening of the epidermis at palmar and plantar surfaces. Clinical and genetic features of isolated and complex PPKs have been reviewed in part I of this 2-part review. Here we focus on clinical and molecular classification of syndromic PPKs which are recognized by additional extracutaneous manifestations, in particular deafness, specific mucosal lesions, cardiomyopathy, inborn errors of metabolism, involvement of internal organs or disorders of sexual development. Other genetic diseases, which may show palmoplantar involvement, such as selected subtypes of hereditary epidermolysis bullosa, various hereditary ichthyoses and other keratinization disorders, several ectodermal dysplasias and some multisystem genetic disorders, are also briefly summarized. PPK diagnosis is based on inheritance pattern, age at onset, morphology, distribution and severity of hyperkeratosis, pattern of additional dermatological and systemic manifestations and laboratory findings. Molecular analysis is at present the gold standard to confirm the diagnosis in PPK forms due to mutations in known causative genes. No specific and curative therapy is currently available for PPKs which highly impair patients' quality of life. Topical treatments are symptomatic and offer only temporary relief. Among systemic treatments, retinoids improve disease symptoms in the majority of patients.

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Clinical and mutational investigations of tyrosinemia type II in Northern Tunisia: Identification and structural characterization of two novel TAT mutations

Cited by 24 publications

References 25 publications

Tyrosine aminotransferase: biochemical and structural properties and molecular dynamics simulations

Tyrosine aminotransferase: biochemical and structural properties and molecular dynamics simulations

Relaxed Evolution in the Tyrosine Aminotransferase Gene Tat in Old World Fruit Bats (Chiroptera: Pteropodidae)

Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas – Diagnostic algorithm and principles of therapy

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