RARE DISEASE
Hawkinsinuria
Hawkinsinuria
Hawkinsinuria
Synonyms: 4-HPPD deficiency, 4-alpha-hydroxyphenylpyruvate hydroxylase deficiency, 4-hydroxyphenylpyruvic acid dioxygenase deficiency
Synonyms: 4-HPPD deficiency, 4-alpha-hydroxyphenylpyruvate hydroxylase deficiency, 4-hydroxyphenylpyruvic acid dioxygenase deficiency
Synonyms: 4-HPPD deficiency, 4-alpha-hydroxyphenylpyruvate hydroxylase deficiency, 4-hydroxyphenylpyruvic acid dioxygenase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Hawkinsinuria is a rare autosomal dominant disorder of tyrosine metabolism caused by heterozygous mutations in the HPD gene, impairing the conversion of 4-hydroxyphenylpyruvate to homogentisate [1][6]. Clinical features include failure to thrive, metabolic acidosis, sparse hair, and urinary excretion of hawkinsin, typically emerging around weaning (4-6 months) [6][9]. Diagnosis involves urine organic acid analysis, elevated tyrosine levels, and genetic testing [3][6]. Management focuses on tyrosine/phenylalanine restriction, ascorbic acid supplementation, and N-acetylcysteine to address glutathione depletion [1][11], with symptoms often improving by age 1-2 years [4][9].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
31 drug discovery papers about Hawkinsinuria, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
31 drug discovery papers about Hawkinsinuria, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-05-16 | Disease associated missense substitutions disrupt structural stability and catalytic function of 4-hydroxyphenylpyruvate dioxygenase.
4-Hydroxylphenylpyruvate dioxygenase (HPPD) is a crucial enzyme in the tyrosine catabolic pathway, catalyzing the conversion of 4-hydroxylphenylpyruvate (HPP) to homogentisate (HG). Missense substitutions in HPPD are associated with type III tyrosinemia and hawkinsinuria. This study investigated disease-related variants in terms of their roles in HPPD structure stability and function. Our whole-cell assay showed a loss of soluble protein expression for G154S, Y160C, and I267F variants, suggesting that the three locations at the domain interface can be critical for proper protein folding. The A33T, A268V, and I335M variants exhibited low soluble protein expression and reduced bioactivity, indicating the three locations at their specific structural motifs affect protein folding but can be less effective. The biochemical analysis found that the N241S variant underwent an uncoupled reaction, forming an oxepinone intermediate that reacts with cysteine and forms the hawkinsin adduct. The A33T and V212M variants, which produced no intermediate product, exhibited similar substrate binding affinity as WT enzymes, but they had decreased structural stability and HG production (aligned with bioassay findings). The reduced structural stability and HG production, and the loss of substrate binding with HPPD-Co(II) complex for the A268V variant suggested that its location is related to the stable conformation of the metal binding motif. The reduced substrate binding affinity and catalytic efficiency for V340L variant suggested the effect at the active site entrance. This study showed the molecular underpinnings of how disease-related substitutions at specific structural locations affect the structural stability and function of HPPD.
2025-07-07 | Competitions for tyrosine breakdown: In synthetic microbial communities and between a gut microbial pathway and a human pathway
ABSTRACT Tyrosine, a versatile amino acid that undergoes diverse transformations to produce both beneficial and detrimental metabolites. The modulation of these metabolites results from direct competition among different metabolic pathways responsible for the breakdown of tyrosine whether it be the competition between distinct microbes or the rivalry between a microbe and its host. The fight between microbes for the available tyrosine might drive potential changes to the communities present in various environments. In contrast, if the similar contest for tyrosine is presented between a gut microbial pathway and a human pathway, it can hold potential to affect the human health. In this work, we present various metabolic outcomes of tyrosine within synthetic microbial communities which are prominently driven by specific enzyme activities of tyrosine breakdown pathways. Additionally, we developed a metabolic diversion of the human tyrosine breakdown pathway facilitated by a gut microbial enzyme. This approach holds promise as a novel strategy to develop potential therapeutic interventions in future for addressing metabolic disorders like tyrosinemias (I, II, III), hawkinsinuria, and alkaptonuria, associated with the human tyrosine breakdown pathway.
2024-03-01 | Abstract 1891 Exploring Tyrosine Metabolism: Examining the implications of competition within a microbial community and the health consequences arising from the rivalry between a gut microbial pathway and the human pathway
Tyrosine, a versatile amino acid crucial for protein synthesis, undergoes diverse conversions leading to both beneficial and detrimental metabolites. The modulation of these metabolite levels results from direct competition among different metabolic pathways responsible for tyrosine breakdown, whether it be the competition between distinct microbes or the rivalry between a microbe and its host. This study aims to understand the breakdown of tyrosine through two distinct scenarios: 1) within a microbial community, and 2) during a competition between a microbe and a host. Our objectives include understanding the mechanisms of these competitions, discerning the metabolic outcomes, and identifying the efficiency of different pathways. To achieve this, we constructed a synthetic microbial community comprising various E. coli strains, each differing solely by the presence of a specific enzyme from a distinct tyrosine metabolic pathway. To assess metabolic outcomes in these communities, we developed a tool employing a phenotypic assay. Our findings reveal that breakdown product levels vary based on the type and combination of metabolic pathways within the community, with the metabolic outcome directly proportional to strain ratios. The methodologies employed in this study include SDS-PAGE analysis, genetic manipulation, colorimetric assays, phenotypic assays, and HPLC. Moreover, the inability to metabolize tyrosine resulting from a flawed tyrosine breakdown pathway in humans contributed to diverse metabolic disorders such as tyrosinemias (I, II, III), hawkinsinuria, and alkaptonuria. Utilizing the tool derived from our experiments on tyrosine breakdown within a microbial community, we illustrate a potential metabolic diversion of the human tyrosine breakdown pathway facilitated by a gut microbial enzyme. This approach holds promise as a novel therapeutic intervention for addressing metabolic disorders associated with the human tyrosine breakdown pathway. We thank the New College of Interdisciplinary Arts and Sciences (NCIAS) at Arizona State University for the funding support.
2022-10-31 | Metabolic profiles and fingerprints for the investigation of the influence of nitisinone on the metabolism of the yeast Saccharomyces cerevisiae
Abstract Nitisinone (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, NTBC) is considered a potentially effective drug for the treatment of various metabolic diseases associated with disorders of L-tyrosine metabolism however, side-effects impede its widespread use. This work aimed to broaden the knowledge of the influence of NTBC and its metabolites 2-amino-4-(trifluoromethyl)benzoic acid (ATFA), 2-nitro-4-(trifluoromethyl)benzoic acid (NTFA), and cyclohexane-1,3-dione (CHD) on the catabolism of L-tyrosine and other endogenous compounds in Saccharomyces cerevisiae. Based on a targeted analysis performed by LC-ESI-MS/MS, based on multiple reaction monitoring, it was found that the dissipation kinetics of the parent compound and its metabolites are compatible with a first-order reaction mechanism. The same mode of analysis was used to reveal that NTBC metabolites formed in the model organism cause a 15–59% decrease in L-tyrosine, L-tryptophan, and L-phenylalanine compared to the untreated model organism. The overall changes in the metabolism of yeast exposed to NTBC or its derivatives were evaluated by non-targeted analysis via LC-ESI-MS/MS in the ion trap scanning mode. Based on principal components analysis, a statistically significant similarity between metabolic responses of yeast treated with ATFA or NTFA was observed. These findings facilitate further studies investigating the influence of NTBC on the human body and the mechanism of its action.
2019-10-01 | Identification of novel inhibitors of p-hydroxyphenylpyruvate dioxygenase using receptor-based virtual screening
p-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is a potential target for herbicide discovery, which catalyzes the conversion of p-hydroxyphenylpyruvate to homogentisate. Triketone HPPD inhibitors have been widely applied to weed control for many years. To discover potential HPPD inhibitors with novel scaffold, a virtual screening procedure combining pharmacophore model, molecular docking and molecular dynamics (MD) simulation was carried out. The crystal complex (PDB: 6ISD) with sulcotrione was selected to establish the receptor-ligand pharmacophore model (CBP). The verified CBP model with key features and interactions was employed to seek structures with potential inhibitory from ZINC database. The best-fit compounds from pharmacophore screening (2050 compounds) were subsequently subjected to molecular docking with CDOCKER method to identify the binding affinity of inhibitors with amino acid residues in active pocket. Six compounds were obtained as the final hits with the Fe(Ш) coordination and π-π interaction with Phe381 and Phe424. MD results demonstrated that Phe424 made great contributions to binding affinities of all the systems. This work provided powerful insights into the design and development of novel HPPD inhibitor in silico techniques. ZINC000255329531 was identified as the most promising candidate due to its high HPPD inhibition effect (ΔGbind = 25.66 kcal mol−1), in comparison with the commercial triketone HPPD herbicide sulcotrione (ΔGbind = 18.94 kcal mol−1).
2026-05-16 | Disease associated missense substitutions disrupt structural stability and catalytic function of 4-hydroxyphenylpyruvate dioxygenase.
4-Hydroxylphenylpyruvate dioxygenase (HPPD) is a crucial enzyme in the tyrosine catabolic pathway, catalyzing the conversion of 4-hydroxylphenylpyruvate (HPP) to homogentisate (HG). Missense substitutions in HPPD are associated with type III tyrosinemia and hawkinsinuria. This study investigated disease-related variants in terms of their roles in HPPD structure stability and function. Our whole-cell assay showed a loss of soluble protein expression for G154S, Y160C, and I267F variants, suggesting that the three locations at the domain interface can be critical for proper protein folding. The A33T, A268V, and I335M variants exhibited low soluble protein expression and reduced bioactivity, indicating the three locations at their specific structural motifs affect protein folding but can be less effective. The biochemical analysis found that the N241S variant underwent an uncoupled reaction, forming an oxepinone intermediate that reacts with cysteine and forms the hawkinsin adduct. The A33T and V212M variants, which produced no intermediate product, exhibited similar substrate binding affinity as WT enzymes, but they had decreased structural stability and HG production (aligned with bioassay findings). The reduced structural stability and HG production, and the loss of substrate binding with HPPD-Co(II) complex for the A268V variant suggested that its location is related to the stable conformation of the metal binding motif. The reduced substrate binding affinity and catalytic efficiency for V340L variant suggested the effect at the active site entrance. This study showed the molecular underpinnings of how disease-related substitutions at specific structural locations affect the structural stability and function of HPPD.
2025-07-07 | Competitions for tyrosine breakdown: In synthetic microbial communities and between a gut microbial pathway and a human pathway
ABSTRACT Tyrosine, a versatile amino acid that undergoes diverse transformations to produce both beneficial and detrimental metabolites. The modulation of these metabolites results from direct competition among different metabolic pathways responsible for the breakdown of tyrosine whether it be the competition between distinct microbes or the rivalry between a microbe and its host. The fight between microbes for the available tyrosine might drive potential changes to the communities present in various environments. In contrast, if the similar contest for tyrosine is presented between a gut microbial pathway and a human pathway, it can hold potential to affect the human health. In this work, we present various metabolic outcomes of tyrosine within synthetic microbial communities which are prominently driven by specific enzyme activities of tyrosine breakdown pathways. Additionally, we developed a metabolic diversion of the human tyrosine breakdown pathway facilitated by a gut microbial enzyme. This approach holds promise as a novel strategy to develop potential therapeutic interventions in future for addressing metabolic disorders like tyrosinemias (I, II, III), hawkinsinuria, and alkaptonuria, associated with the human tyrosine breakdown pathway.
2024-03-01 | Abstract 1891 Exploring Tyrosine Metabolism: Examining the implications of competition within a microbial community and the health consequences arising from the rivalry between a gut microbial pathway and the human pathway
Tyrosine, a versatile amino acid crucial for protein synthesis, undergoes diverse conversions leading to both beneficial and detrimental metabolites. The modulation of these metabolite levels results from direct competition among different metabolic pathways responsible for tyrosine breakdown, whether it be the competition between distinct microbes or the rivalry between a microbe and its host. This study aims to understand the breakdown of tyrosine through two distinct scenarios: 1) within a microbial community, and 2) during a competition between a microbe and a host. Our objectives include understanding the mechanisms of these competitions, discerning the metabolic outcomes, and identifying the efficiency of different pathways. To achieve this, we constructed a synthetic microbial community comprising various E. coli strains, each differing solely by the presence of a specific enzyme from a distinct tyrosine metabolic pathway. To assess metabolic outcomes in these communities, we developed a tool employing a phenotypic assay. Our findings reveal that breakdown product levels vary based on the type and combination of metabolic pathways within the community, with the metabolic outcome directly proportional to strain ratios. The methodologies employed in this study include SDS-PAGE analysis, genetic manipulation, colorimetric assays, phenotypic assays, and HPLC. Moreover, the inability to metabolize tyrosine resulting from a flawed tyrosine breakdown pathway in humans contributed to diverse metabolic disorders such as tyrosinemias (I, II, III), hawkinsinuria, and alkaptonuria. Utilizing the tool derived from our experiments on tyrosine breakdown within a microbial community, we illustrate a potential metabolic diversion of the human tyrosine breakdown pathway facilitated by a gut microbial enzyme. This approach holds promise as a novel therapeutic intervention for addressing metabolic disorders associated with the human tyrosine breakdown pathway. We thank the New College of Interdisciplinary Arts and Sciences (NCIAS) at Arizona State University for the funding support.
2022-10-31 | Metabolic profiles and fingerprints for the investigation of the influence of nitisinone on the metabolism of the yeast Saccharomyces cerevisiae
Abstract Nitisinone (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, NTBC) is considered a potentially effective drug for the treatment of various metabolic diseases associated with disorders of L-tyrosine metabolism however, side-effects impede its widespread use. This work aimed to broaden the knowledge of the influence of NTBC and its metabolites 2-amino-4-(trifluoromethyl)benzoic acid (ATFA), 2-nitro-4-(trifluoromethyl)benzoic acid (NTFA), and cyclohexane-1,3-dione (CHD) on the catabolism of L-tyrosine and other endogenous compounds in Saccharomyces cerevisiae. Based on a targeted analysis performed by LC-ESI-MS/MS, based on multiple reaction monitoring, it was found that the dissipation kinetics of the parent compound and its metabolites are compatible with a first-order reaction mechanism. The same mode of analysis was used to reveal that NTBC metabolites formed in the model organism cause a 15–59% decrease in L-tyrosine, L-tryptophan, and L-phenylalanine compared to the untreated model organism. The overall changes in the metabolism of yeast exposed to NTBC or its derivatives were evaluated by non-targeted analysis via LC-ESI-MS/MS in the ion trap scanning mode. Based on principal components analysis, a statistically significant similarity between metabolic responses of yeast treated with ATFA or NTFA was observed. These findings facilitate further studies investigating the influence of NTBC on the human body and the mechanism of its action.
2019-10-01 | Identification of novel inhibitors of p-hydroxyphenylpyruvate dioxygenase using receptor-based virtual screening
p-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is a potential target for herbicide discovery, which catalyzes the conversion of p-hydroxyphenylpyruvate to homogentisate. Triketone HPPD inhibitors have been widely applied to weed control for many years. To discover potential HPPD inhibitors with novel scaffold, a virtual screening procedure combining pharmacophore model, molecular docking and molecular dynamics (MD) simulation was carried out. The crystal complex (PDB: 6ISD) with sulcotrione was selected to establish the receptor-ligand pharmacophore model (CBP). The verified CBP model with key features and interactions was employed to seek structures with potential inhibitory from ZINC database. The best-fit compounds from pharmacophore screening (2050 compounds) were subsequently subjected to molecular docking with CDOCKER method to identify the binding affinity of inhibitors with amino acid residues in active pocket. Six compounds were obtained as the final hits with the Fe(Ш) coordination and π-π interaction with Phe381 and Phe424. MD results demonstrated that Phe424 made great contributions to binding affinities of all the systems. This work provided powerful insights into the design and development of novel HPPD inhibitor in silico techniques. ZINC000255329531 was identified as the most promising candidate due to its high HPPD inhibition effect (ΔGbind = 25.66 kcal mol−1), in comparison with the commercial triketone HPPD herbicide sulcotrione (ΔGbind = 18.94 kcal mol−1).
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