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Abstract <p>Pterin deaminase and sepiapterin deaminase are key members of the amidohydrolase superfamily and play essential roles in pteridine metabolism across a wide range of biological systems. Pterin deaminase catalyzes the deamination of pterins, contributing to the regulation of purine and pyrimidine metabolism, whereas sepiapterin deaminase is specifically involved in the degradation of sepiapterin, a critical intermediate in the tetrahydrobiopterin (BH4) biosynthetic pathway. These enzymes are distributed throughout prokaryotic and eukaryotic organisms and display diverse substrate specificity, metal dependency, and enzymatic stability. Pterin deaminase has been identified in bacterial and fungal species, as well as in mammalian liver tissues, where it plays a role in folate metabolism and cellular signalling. In contrast, sepiapterin deaminase is predominantly found in vertebrate tissues with a high BH4 demand, particularly in the neurological and vascular systems. Structural analyses reveal that both enzymes share the conserved metal-binding characteristics of the amidohydrolase superfamily, with pterin deaminase being a zinc-dependent metalloenzyme. Despite sharing the (β/α)₈-barrel fold and metal-binding catalytic core, subtle variations in active-site residues, such as the substitution of histidine with cysteine, determines their catalytic behavior, metal preference, and redox sensitivity. Comparative kinetic and structural analyses revealed that pterin deaminase displayed broader catalytic flexibility and higher metal tolerance, whereas sepiapterin deaminase maintained strict substrate selectivity and redox regulation. These adaptive differences reflect an evolutionary transition from general pterin degradation to specialized cofactor maintenance and pigment biosynthesis. Beyond their biochemical distinctiveness, both enzymes exhibit emerging biomedical and biotechnological significance. Pterin deaminase in folate catabolism and potential antitumor applications and sepiapterin deaminase in neurotransmitter regulation and pigment-associated disorders. This review provides a detailed structural, catalytic, and physiological perspectives to highlight the evolutionary divergence of pterin deaminase and sepiapterin deaminase within the amidohydrolase fold, and their growing relevance in metabolic and biomedical research.</p> Key points <p>• <i>Pterin deaminase and Sepiapterin deaminase play important but different roles in the pteridine metabolic network.</i></p> <p>• <i>Pterin Deaminase’s thermostability and substrate versatility make it a promising biocatalyst for green chemistry, pharmaceutical synthesis, and diagnostic biosensors.</i></p> <p>• <i>Sepiapterin deaminase -like enzymes in bacteria appear stress-inducible, with expression modulated by oxidative response factors such as SoxRS and fumarate-nitrate reductase (FNR), an adaptive role in redox regulation and biofilm formation.</i></p>

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Structural and mechanistic insights into the divergence of pterin deaminase and sepiapterin deaminase

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月16日

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  • Nivetha Shanmuganathan,
  • Sasireka Manikandan,
  • Jerimon Johnson,
  • Sabaridaran Balasubramani,
  • Angayarkanni Jayaraman,
  • Sruthi Paleri,
  • Theertha Ranjith,
  • Thasleema Parveen A

摘要

Abstract

Pterin deaminase and sepiapterin deaminase are key members of the amidohydrolase superfamily and play essential roles in pteridine metabolism across a wide range of biological systems. Pterin deaminase catalyzes the deamination of pterins, contributing to the regulation of purine and pyrimidine metabolism, whereas sepiapterin deaminase is specifically involved in the degradation of sepiapterin, a critical intermediate in the tetrahydrobiopterin (BH4) biosynthetic pathway. These enzymes are distributed throughout prokaryotic and eukaryotic organisms and display diverse substrate specificity, metal dependency, and enzymatic stability. Pterin deaminase has been identified in bacterial and fungal species, as well as in mammalian liver tissues, where it plays a role in folate metabolism and cellular signalling. In contrast, sepiapterin deaminase is predominantly found in vertebrate tissues with a high BH4 demand, particularly in the neurological and vascular systems. Structural analyses reveal that both enzymes share the conserved metal-binding characteristics of the amidohydrolase superfamily, with pterin deaminase being a zinc-dependent metalloenzyme. Despite sharing the (β/α)₈-barrel fold and metal-binding catalytic core, subtle variations in active-site residues, such as the substitution of histidine with cysteine, determines their catalytic behavior, metal preference, and redox sensitivity. Comparative kinetic and structural analyses revealed that pterin deaminase displayed broader catalytic flexibility and higher metal tolerance, whereas sepiapterin deaminase maintained strict substrate selectivity and redox regulation. These adaptive differences reflect an evolutionary transition from general pterin degradation to specialized cofactor maintenance and pigment biosynthesis. Beyond their biochemical distinctiveness, both enzymes exhibit emerging biomedical and biotechnological significance. Pterin deaminase in folate catabolism and potential antitumor applications and sepiapterin deaminase in neurotransmitter regulation and pigment-associated disorders. This review provides a detailed structural, catalytic, and physiological perspectives to highlight the evolutionary divergence of pterin deaminase and sepiapterin deaminase within the amidohydrolase fold, and their growing relevance in metabolic and biomedical research.

Key points

• Pterin deaminase and Sepiapterin deaminase play important but different roles in the pteridine metabolic network.

• Pterin Deaminase’s thermostability and substrate versatility make it a promising biocatalyst for green chemistry, pharmaceutical synthesis, and diagnostic biosensors.

• Sepiapterin deaminase -like enzymes in bacteria appear stress-inducible, with expression modulated by oxidative response factors such as SoxRS and fumarate-nitrate reductase (FNR), an adaptive role in redox regulation and biofilm formation.