Metabolic Studies on Two Patients with Nonhepatic Tyrosinemia Using Deuterated Tyrosine Loads

MATERIALS AND METHODSdrolase (EC 3.7.1.2) has been demonstrated in several patients (18) and is now felt to be the primary enzyme defect in this disease.Tyrosinemia type II has been described in over twenty patients, most of whom have manifest the Richner-Hanhart syndrome with severe persistent keratitis and more variable hyperkeratosis on the fmgers and palms of the hands and soles of the feet. These lesions respond completely to dietary tyrosine restriction. Blood tyrosine is greatly elevated and there is massive tyrosyluria. Absent activity of hepatic cytosol TAT has been demonstrated in two patients (9, 16) and a milder deficiency has been reported in two other patients, in liver (Il) and fibroblasts (4) respectively.Another form of tyrosinemia has been reported in two childrep. with severe metabolic acidosis who excreted the unusual tyrosine metabolites hawkinsin and cis-and trans-4-hydroxycyclohexylacetic acids in the urine (3,22,26). The' primary abnormality is thought to be in the rearrangement of an intermediate formed in the 4HPPD reaction.We now report a case of persistent tyrosinemia and tyrosyluria associated with deficient activity of 4HPPD in liver. The clinical picture was characterized by sporadic ataxia and drowsiness in a child who was otherwise normal. Summary SpeculationA 17-month-old girl, with acute intermittent ataxia and drowsiness, had hypertyrosinemia (serum tyrosine, 62 JLmole/dl) and phenolic aciduria in the absence of hepatic, renal, eye or skin lesions. Serum methionine and urinary~-aminolevulinic acid concentrations were normal. Her psychomotor development was also normal. Protein restriction and vitamin C therapy failed to correct the biochemical abnormality. Liver biopsy was histologically normal.Analysis of the enzymes in the liver biopsy, taken at 25 months of age, showed no detectable activity of 4-hydroxyphenylpyruvate dioxygenase (4HPPD), either in whole homogenate or cytosol fraction. Mixing experiments revealed no inhibitor of either 4HPPD or tyrosine aminotransferase (TAT).TAT in unfractionated liver was 0.23 JLmole/mg protein/h (control, 0.10-0.30 JLmole/mg protein/h; n = 5). In mitochondria, TAT was 0.24 JLmole/mg protein/h (control, 0.09-0.12 JLmole/mg protein/h; n = 3) whereas in cytosol fraction it was 0.23 JLmole/mg protein/h (control, 0.27-0.44 JLmole/mg protein/h; n = 3). Glutamate dehydrogenase activity appeared in the cytosol fraction suggesting some rupture of mitochondria during fractionation of the patient's liver and indicating that true cytosol TAT might be somewhat lower than indicated; however, the kinetics of the patient's cytosol TAT were normal: Km for tyrosine, 4.5 X 10-3 M (control, 4.0 X 10-3 M); Km for a-ketoglutarate, 98 X 10-6 M (control,75 X 10-6 M); approximate Km for pyridoxal phosphate, 2

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“…This has previously been suggested by Pelet et ai. (23) with reference to four other patients (5,10,12).…”

Section: Giardini Et Almentioning

confidence: 99%

Chronic Tyrosinemia Associated with 4-Hydroxyphenylpyruvate Dioxygenase Deficiency with Acute Intermittent Ataxia and without Visceral and Bone Involvement

et al. 1983

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“…Therefore, we purified p-Tyr, DL-o-Tyr, and L-DOPA before their use for kinetic analyses. p-Tyr (Regis Chemical Co.) was purified by recrystallization from a minimal volume of boiling water as previously described (15). DL-o-Tyrosine (o-Tyr, Fluka, Ͼ96.0% nonaqueous titration) was dissolved in 0.1% trifluoroacetic acid and injected (250 l aliquots) onto a thoroughly washed semipreparative reverse phase HPLC column (Keystone Scientific Aquasil C18, 250 ϫ 10 mm) equilibrated and eluted (3 ml/min) with water.…”

Section: Methodsmentioning

confidence: 99%

Multiple Quality Control Pathways Limit Non-protein Amino Acid Use by Yeast Cytoplasmic Phenylalanyl-tRNA Synthetase

Moghal

Hwang

Faull

et al. 2016

Journal of Biological Chemistry

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Non-protein amino acids, particularly isomers of the proteinogenic amino acids, present a threat to proteome integrity if they are mistakenly inserted into proteins. Quality control during aminoacyl-tRNA synthesis reduces non-protein amino acid incorporation by both substrate discrimination and proofreading. For example phenylalanyl-tRNA synthetase (PheRS) proofreads the non-protein hydroxylated phenylalanine derivative m-Tyr after its attachment to tRNA Phe . We now show in Saccharomyces cerevisiae that PheRS misacylation of tRNA Phe with the more abundant Phe oxidation product o-Tyr is limited by kinetic discrimination against o-Tyr-AMP in the transfer step followed by o-Tyr-AMP release from the synthetic active site. This selective rejection of a non-protein aminoacyl-adenylate is in addition to known kinetic discrimination against certain noncognates in the activation step as well as catalytic hydrolysis of mispaired aminoacyl-tRNA Phe species. We also report an unexpected resistance to cytotoxicity by a S. cerevisiae mutant with ablated post-transfer editing activity when supplemented with o-Tyr, cognate Phe, or Ala, the latter of which is not a substrate for activation by this enzyme. Our phenotypic, metabolomic, and kinetic analyses indicate at least three modes of discrimination against non-protein amino acids by S. cerevisiae PheRS and support a non-canonical role for SccytoPheRS post-transfer editing in response to amino acid stress.

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Dietary Management of Oculocutaneous Tyrosinemia in an 11-Year-Old Child

Ney¹

1983

Arch Pediatr Adolesc Med

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Metabolic Studies on Two Patients with Nonhepatic Tyrosinemia Using Deuterated Tyrosine Loads

Cited by 17 publications

References 5 publications

Chronic Tyrosinemia Associated with 4-Hydroxyphenylpyruvate Dioxygenase Deficiency with Acute Intermittent Ataxia and without Visceral and Bone Involvement

Chronic Tyrosinemia Associated with 4-Hydroxyphenylpyruvate Dioxygenase Deficiency with Acute Intermittent Ataxia and without Visceral and Bone Involvement

Multiple Quality Control Pathways Limit Non-protein Amino Acid Use by Yeast Cytoplasmic Phenylalanyl-tRNA Synthetase

Dietary Management of Oculocutaneous Tyrosinemia in an 11-Year-Old Child

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