- Hereditary tyrosinemia type I-associated mutations in fumarylacetoacetate hydrolase reduce the enzyme stability and increase its aggregation rate. [Journal Article]
- JBJ Biol Chem 2019 Jul 12
- More than 100 mutations in the gene encoding fumarylacetoacetate hydrolase (FAH) cause hereditary tyrosinemia type I (HT1), a metabolic disorder characterized by elevated blood levels of tyrosine. So…
More than 100 mutations in the gene encoding fumarylacetoacetate hydrolase (FAH) cause hereditary tyrosinemia type I (HT1), a metabolic disorder characterized by elevated blood levels of tyrosine. Some of these mutations are known to decrease FAH catalytic activity, but the mechanisms of FAH mutation-induced pathogenicity remain poorly understood. Here, using diffusion ordered NMR spectroscopy, cryo-EM, and CD analyses, along with site-directed mutagenesis, enzymatic assays, and molecular dynamics simulations, we investigated the putative role of thermodynamic and kinetic stability in wild type (WT) FAH and a representative set of 19 missense mutations identified in individuals with HT1. We found that at physiological temperatures and concentrations, WT FAH is in equilibrium between a catalytically active dimer and a monomeric species, with the latter being inactive and prone to oligomerization and aggregation. We also found that the majority of the deleterious mutations reduce the kinetic stability of the enzyme and always accelerate the FAH aggregation pathway. Depending mainly on the position of the amino acid in the structure, pathogenic mutations either reduced the dimer population or decreased the energy barrier that separates the monomer from the aggregate. The mechanistic insights reported here pave the way for the development of pharmacological chaperones that target FAH to tackle the severe disease HT1.
- HPD overexpression predicts poor prognosis in breast cancer. [Journal Article]
- PRPathol Res Pract 2019 Jun 28; :152524
- CONCLUSIONS: Our findings indicate that HPD may be a useful prognostic predictor, and a potential therapeutic target for patients with breast cancer.
- Validation of a therapeutic range for nitisinone in patients treated for tyrosinemia type 1 based on reduction of succinylacetone excretion. [Journal Article]
- JRJIMD Rep 2019; 46(1):75-78
- The drug nitisinone (NTBC; Orfadin, Vienna, Austria) has been used for the treatment of hereditary tyrosinemia type-1 since 1991. Nitisinone effectively blocks the metabolism of tyrosine to prevent t…
The drug nitisinone (NTBC; Orfadin, Vienna, Austria) has been used for the treatment of hereditary tyrosinemia type-1 since 1991. Nitisinone effectively blocks the metabolism of tyrosine to prevent the formation of the toxic compound succinylacetone (and precursor fumarylacetoacetate) in affected children. Monitoring of plasma drug levels and urine succinylacetone can be used to assess compliance and adequate dose of drug. We present retrospective data from patient monitoring for over 10 years that provide validation of a target therapeutic range for nitisinone of 40 to 60 μmol/L. The target nitisinone range is justified as valid based on reduction of succinylacetone excretion. There was no statistical significance in succinylacetone excretion in mmol/mol creatinine above a level of 40 μmol/L plasma NTBC (P > 0.05).
- Senescence suppressed proliferation of host hepatocytes is precondition for liver repopulation. [Journal Article]
- BBBiochem Biophys Res Commun 2019 Aug 20; 516(2):591-598
- In the fumarylacetoacetate hydrolase deficient (Fah-/-) mouse, massive liver repopulation can be easily obtained after transplanted hepatocytes. Understanding the mechanisms of complete liver repopul…
In the fumarylacetoacetate hydrolase deficient (Fah-/-) mouse, massive liver repopulation can be easily obtained after transplanted hepatocytes. Understanding the mechanisms of complete liver repopulation in Fah-/- mice will be useful for future clinical application. Here, we found that the endogenous hepatocytes in liver of Fah-/- mice undertook senescence during the time of tyrosinemia symptoms. Increase of senescent hepatocytes in Fah-/- mice provided proliferative advantage to the transplanted hepatocytes. Importantly, senescent hepatocytes upregulated the expression of extracellular matrix enzyme, contributing to degradation of extracellular matrix components and weakness of cell adhesion and connection. The liver exhibiting a loose architecture provided the space for the engraftment and expansion of transplanted hepatocytes. These findings underscore the underlying mechanisms of completed liver repopulation in Fah-/- mice. Senescence followed by loose hepatic parenchyma is a preconditioning for liver repopulation, which would be a promising strategy to achieve therapeutic liver repopulation in clinical settings.
- Interference of hydroxyphenylpyruvic acid, hydroxyphenyllactic acid and tyrosine on routine serum and urine clinical chemistry assays; implications for biochemical monitoring of patients with alkaptonuria treated with nitisinone. [Journal Article]
- CBClin Biochem 2019 Jun 20
- CONCLUSIONS: In patients with AKU or on nitisinone treatment and HT-1 patients on nitisinone, urine strip chemistry testing should be used sparingly, if at all, to avoid false negative reporting. It is recommended that urine assays should be organised with a suitable specialist laboratory.
- Live donor liver transplantation for type 1 tyrosinemia: An analysis of 15 patients. [Journal Article]
- PTPediatr Transplant 2019 Jun 03; :e13498
- Type 1 tyrosinemia is a rare metabolic disorder of the tyrosine degradation pathway. Due to the rarity of the disease, the best evidence literature offers is limited to guidelines based on expert opi…
Type 1 tyrosinemia is a rare metabolic disorder of the tyrosine degradation pathway. Due to the rarity of the disease, the best evidence literature offers is limited to guidelines based on expert opinions and optimal treatment is still a debate. LT serves as a definitive treatment of the defective metabolic pathway in the liver along with other serious disease manifestations such as LF and HCC. Nitisinone is a relatively new agent that is currently recommended for the medical management of the disease. Its mechanism of action is well understood, and efficacy is well established when started presymptomatically. This study aims to evaluate outcomes of 15 patients with type 1 tyrosinemia who underwent LT in nitisinone era and discuss its effect on prevention of HCC. A LT database of 1037 patients was reviewed. Data from 15 patients with type 1 tyrosinemia were retrospectively analyzed. All the patients except one were treated with nitisinone prior to LT. Most common indications for LT were LF and suspicious nodules. Seven patients had HCC. Mortality rate was 20% (n = 3). Nitisinone treatment has opened new horizons in the management of type 1 tyrosinemia, but LT still remains the only option for the patients developing LF and in the event of HCC. Neonatal screening programs utilizing blood succinyl acetone as the marker should be encouraged especially in the countries, such as Turkey, with high prevalence of consanguineous marriages.
- Imaging liver nodules in tyrosinemia type-1: A retrospective review of 16 cases in a tertiary pediatric hospital. [Journal Article]
- EJEur J Radiol 2019; 116:41-46
- CONCLUSIONS: Multiple fatty nodules can be seen in HT1 patients and in some patients, the regenerative and dysplastic nodules can disappear during the follow-up period.
- Correction: Cas9-nickase-mediated genome editing corrects hereditary tyrosinemia in rats. [Journal Article]
- JBJ Biol Chem 2019 May 24; 294(21):8348
- In-Silico analysis of missense SNPs in Human HPPD gene associated with Tyrosinemia type III and Hawkinsinuria. [Journal Article]
- CBComput Biol Chem 2019; 80:284-291
- HPPD gene codes a dioxygenase enzyme involved in catalysis of different molecules such as tyrosine and phenylalanine by oxidizing them to produce energy. A single change in protein can trigger seriou…
HPPD gene codes a dioxygenase enzyme involved in catalysis of different molecules such as tyrosine and phenylalanine by oxidizing them to produce energy. A single change in protein can trigger serious genetic disorders like Tyrosinemia type III and Hawkinsinuria. This study aims to identify the functional missense SNPs of the HPPD gene by using multiple computational tools. All deleterious missense SNPs retrieved from Ensembl and OMIM database were evaluated through six different software. Ultimately, out of 148 missense SNPs, only 27 were confirmed as diseasecausing SNPs by developing a consensus approach. These damaging SNPs were further examined to evaluate their impact on protein stability and energy including their evolutionary conservation. Native and mutated proteins structures were also designed and superimposed by I-TASSER and PyMol respectively. This work results in narrowing down missense SNPs which are still not confirmed experimentally and demands the confirmation by GWAS data. Thus, these missense SNPs could directly or indirectly destabilize the amino acid interactions causing functional deviations of protein.
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- [Clinical and genetic analysis of a patient with tyrosinemia type I but without elevated succinylacetone]. [Journal Article]
- ZYZhonghua Yi Xue Yi Chuan Xue Za Zhi 2019 May 10; 36(5):472-476
- CONCLUSIONS: For children with tyrosinemia type I, detection of urine succinylacetone by gas phase mass spectrometry can be negative. The diagnosis of tyrosinemia type I must rely on genetic testing and/or enzymatic assaying.