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Feksa, Luciane Rosa; Cornelio, Andrea Renata; Rech, Virgínia Cielo; Dutra-Filho, Carlos Severo; Wyse, Ângela T. S.; Wajner, Moaçir; Wannmacher, Clóvis Milton Duval

doi:10.1023/a:1020351800882

Cited by 16 publications

(2 citation statements)

References 30 publications

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“…Phe is an allosteric inhibitor of M 1 -PYK that causes a decrease in this enzyme's apparent affinity for PEP (). The physiological relevance of this regulation is not fully understood but may have implications in phenylketonuria ( − ). Biochemically, the Phe inhibition of M 1 -PYK from rabbit has become a model system for the study of allosteric enzymes.…”

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confidence: 99%

Differentiating a Ligand's Chemical Requirements for Allosteric Interactions from Those for Protein Binding. Phenylalanine Inhibition of Pyruvate Kinase^,

et al. 2006

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The isoform of pyruvate kinase from brain and muscle of mammals (M(1)-PYK) is allosterically inhibited by phenylalanine. Initial observations in this model allosteric system indicate that Ala binds competitively with Phe, but elicits a minimal allosteric response. Thus, the allosteric ligand of this system must have requirements for eliciting an allosteric response in addition to the requirements for binding. Phe analogues have been used to dissect what chemical properties of Phe are responsible for eliciting the allosteric response. We first demonstrate that the l-2-aminopropanaldehyde substructure of the amino acid ligand is primarily responsible for binding to M(1)-PYK. Since the allosteric response to Ala is minimal and linear addition of methyl groups beyond the beta-carbon increase the magnitude of the allosteric response, we conclude that moieties beyond the beta-carbon are primarily responsible for allostery. Instead of an all-or-none mechanism of allostery, these findings support the idea that the bulk of the hydrophobic side chain, but not the aromatic nature, is the primary determinant of the magnitude of the observed allosteric inhibition. The use of these results to direct structural studies has resulted in a 1.65 A structure of M(1)-PYK with Ala bound. The coordination of Ala in the allosteric amino acid binding site confirms the binding role of the l-2-aminopropanaldehyde substructure of the ligand. Collectively, this study confirms that a ligand can have chemical regions specific for eliciting the allosteric signal in addition to the chemical regions necessary for binding.

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confidence: 99%

Differentiating a Ligand's Chemical Requirements for Allosteric Interactions from Those for Protein Binding. Phenylalanine Inhibition of Pyruvate Kinase^,

et al. 2006

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“…Rat-derived hippocampal and cerebral cortex regions showed that phenylalanine exposure induced oxidative stress by decreasing the levels of reduced glutathione, or GSH, which is an important regulator of antioxidant defense mechanisms ( Fernandes et al, 2010 ). It has been suggested that administration of antioxidant therapeutics may alleviate PKU-related symptoms ( Martinez-Cruz et al, 2002 ), given that oxidative damage could be prevented by the addition of antioxidants and free radical scavengers in the aforementioned studies ( Feksa et al, 2002 ; Fernandes et al, 2010 ; Preissler et al, 2016 ). However, while some data suggests beneficial effects of antioxidant supplementation, other clinical studies argue against it ( Mazzola et al, 2013 ).…”

Section: Neuropathology Of Phenylketonuriamentioning

confidence: 99%

Engineering Organoids for in vitro Modeling of Phenylketonuria

Borges

Broersen

Leandro

et al. 2022

Front. Mol. Neurosci.

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Phenylketonuria is a recessive genetic disorder of amino-acid metabolism, where impaired phenylalanine hydroxylase function leads to the accumulation of neurotoxic phenylalanine levels in the brain. Severe cognitive and neuronal impairment are observed in untreated/late-diagnosed patients, and even early treated ones are not safe from life-long sequelae. Despite the wealth of knowledge acquired from available disease models, the chronic effect of Phenylketonuria in the brain is still poorly understood and the consequences to the aging brain remain an open question. Thus, there is the need for better predictive models, able to recapitulate specific mechanisms of this disease. Human induced pluripotent stem cells (hiPSCs), with their ability to differentiate and self-organize in multiple tissues, might provide a new exciting in vitro platform to model specific PKU-derived neuronal impairment. In this review, we gather what is known about the impact of phenylalanine in the brain of patients and highlight where hiPSC-derived organoids could contribute to the understanding of this disease.

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Examining the blood amino acid status in pretherapeutic patients with hyperphenylalaninemia

Liang

Han

et al. 2019

Clinical Laboratory Analysis

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Background Hyperphenylalaninemia is the most common genetic metabolic disease. Early treatment prevents brain injury effectively. The present study aimed to detect the exact amino acid status of patients with hyperphenylalaninemia before treatment. Methods Data of 116 newborn patients from our Newborn Screening Center and 161 older patients from our clinic before treatment were collected. The content of 17 amino acids in their blood was determined by tandem mass spectrometry and compared with normal controls. Relationship between phenylalanine and other amino acids in patients was analyzed using the smoothing curve fitting and threshold effect analysis. Results Most amino acids in the blood of patients were within the normal range; however, they were different significantly from those of the normal children. Newborn patients showed higher phenylalanine (346.30 vs 45.90 µmol/L), valine (121.50 vs 110.30 µmol/L), citrulline, ornithine and lower tyrosine (52.97 vs 66.12 µmol/L), threonine (68.68 vs 78.21 µmol/L), glutamine levels than observed in normal newborns. Older patients showed significantly higher phenylalanine (844.00 vs 51.82 µmol/L), valine (117.60 vs 110.90 µmol/L), histidine, serine and lower tyrosine (55.97 vs 67.31 µmol/L), threonine (35.94 vs 51.89 µmol/L), alanine, asparagine, glutamic acid, methionine, arginine, glycine, ornithine, glutamine content than found in matched normal children. Tyrosine, valine, ornithine, and threonine in newborn patients and tyrosine, glycine, glutamine, and threonine in older patients had a nonlinear correlation with phenylalanine levels with obvious threshold effect and clear inflection points. Conclusion Significant difference was observed in the amino acid status between pretherapeutic hyperphenylalaninemia patients and normal children. Some amino acids showed notable threshold effect with phenylalanine level in a nonlinear pattern.

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Cited by 16 publications

References 30 publications

Differentiating a Ligand's Chemical Requirements for Allosteric Interactions from Those for Protein Binding. Phenylalanine Inhibition of Pyruvate Kinase^,

Differentiating a Ligand's Chemical Requirements for Allosteric Interactions from Those for Protein Binding. Phenylalanine Inhibition of Pyruvate Kinase^,

Engineering Organoids for in vitro Modeling of Phenylketonuria

Examining the blood amino acid status in pretherapeutic patients with hyperphenylalaninemia

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Untitled

Cited by 16 publications

References 30 publications

Differentiating a Ligand's Chemical Requirements for Allosteric Interactions from Those for Protein Binding. Phenylalanine Inhibition of Pyruvate Kinase,

Differentiating a Ligand's Chemical Requirements for Allosteric Interactions from Those for Protein Binding. Phenylalanine Inhibition of Pyruvate Kinase,

Engineering Organoids for in vitro Modeling of Phenylketonuria

Examining the blood amino acid status in pretherapeutic patients with hyperphenylalaninemia

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Differentiating a Ligand's Chemical Requirements for Allosteric Interactions from Those for Protein Binding. Phenylalanine Inhibition of Pyruvate Kinase^,

Differentiating a Ligand's Chemical Requirements for Allosteric Interactions from Those for Protein Binding. Phenylalanine Inhibition of Pyruvate Kinase^,