A liver urocanase deficiency

doi:10.1016/0026-0495(80)90209-7

Metabolism

Volume 29, Issue 11, November 1980, Pages 1013-1019

https://doi.org/10.1016/0026-0495(80)90209-7 Get rights and content

Abstract

Two sisters with a rare inborn error of histidine metabolism resulting from urocanase deficiency are being presented. The more common form of familial histidinemia due to histidase deficiency is excluded. The urocanase deficiency is proven by demonstrating increased excretion of precursor metabolites and decreased excretion of metabolites of the product of the urocanase enzyme action. Further, the strongest evidence for the urocanase defect rests on the demonstration of urocanase deficiency and normal histidase activity in liver.

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Cited by (8)

Untargeted metabolomics identifies unique though benign biochemical changes in patients with pathogenic variants in UROC1
2019, Molecular Genetics and Metabolism Reports
Citation Excerpt :
The family of urocanases is highly conserved across multiple species and appears to be almost exclusively expressed in the liver [3]. Urocanic aciduria has been described in association with varying degrees of intellectual disability, though from very early on, this association has been somewhat tenuous [4–6]. Yoshide et al. for instance, first reported the case of a 16 year old young man with severe intellectual disability and significant urocanic aciduria in the setting of significantly decreased liver urocanase activity on biopsy [4].
Urocanic aciduria is caused by a deficiency in the enzyme urocanase (E.C. 4.2.1.49) encoded by the gene UROC1. In the past, deficiency of urocanase has been associated with intellectual disability in a few case studies with some suggestion that the enzyme deficiency was the causative etiology. Here, we describe two phenotypically normal siblings with compound heterozygous pathogenic variants in UROC1 and characteristic biochemical evidence of urocanase deficiency collected utilizing untargeted metabolomic analysis. These findings suggest that urocanic aciduria may represent an otherwise benign biochemical phenotype and that those individuals with concurrent developmental delay should continue to be evaluated for other underlying causes for their symptoms.
Moderate UV Exposure Enhances Learning and Memory by Promoting a Novel Glutamate Biosynthetic Pathway in the Brain
2018, Cell
Citation Excerpt :
These discoveries expand knowledge of other biosynthetic GLU pathway in neurons beyond the quintessential pathways, such as the tricarboxylic acid cycle originating with glucose and the GLU-glutamine cycle between neurons and astrocytes (Bélanger et al., 2011). The presence of HIS-UCA-GLU pathway in the CNS is supported by the clinical findings showing that histidinemia and urocanic aciduria, which are autosomal recessive metabolic disorders due to histidase and urocanase deficiency respectively, are both associated with multiple central developmental symptoms, including learning difficulties, speech or language disturbances, subnormal intelligence, and mental retardation (Davies and Robinson, 1963; Espinós et al., 2009; Kalafatic et al., 1980; Lott et al., 1970; Raisová and Hyánek, 1986), presumably because of lower GLU synthesis in neurons during brain development, based upon our findings. This study indicates that the single-cell MS technology is a valuable tool to study novel metabolic pathways in the brain at the single-cell level.
Sunlight exposure is known to affect mood, learning, and cognition. However, the molecular and cellular mechanisms remain elusive. Here, we show that moderate UV exposure elevated blood urocanic acid (UCA), which then crossed the blood-brain barrier. Single-cell mass spectrometry and isotopic labeling revealed a novel intra-neuronal metabolic pathway converting UCA to glutamate (GLU) after UV exposure. This UV-triggered GLU synthesis promoted its packaging into synaptic vesicles and its release at glutamatergic terminals in the motor cortex and hippocampus. Related behaviors, like rotarod learning and object recognition memory, were enhanced after UV exposure. All UV-induced metabolic, electrophysiological, and behavioral effects could be reproduced by the intravenous injection of UCA and diminished by the application of inhibitor or short hairpin RNA (shRNA) against urocanase, an enzyme critical for the conversion of UCA to GLU. These findings reveal a new GLU biosynthetic pathway, which could contribute to some of the sunlight-induced neurobehavioral changes.
Structure and action of urocanase
2004, Journal of Molecular Biology
Urocanase (EC 4.2.1.49) from Pseudomonas putida was crystallized after removing one of the seven free thiol groups. The crystal structure was solved by multiwavelength anomalous diffraction (MAD) using a seleno-methionine derivative and then refined at 1.14 Å resolution. The enzyme is a symmetric homodimer of 2×557 amino acid residues with tightly bound NAD⁺ cofactors. Each subunit consists of a typical NAD-binding domain inserted into a larger core domain that forms the dimer interface. The core domain has a novel chain fold and accommodates the substrate urocanate in a surface depression. The NAD domain sits like a lid on the core domain depression and points with the nicotinamide group to the substrate. Substrate, nicotinamide and five water molecules are completely sequestered in a cavity. Most likely, one of these water molecules hydrates the substrate during catalysis. This cavity has to open for substrate passage, which probably means lifting the NAD domain. The observed atomic arrangement at the active center gives rise to a detailed proposal for the catalytic mechanism that is consistent with published chemical data. As expected, the variability of the residues involved is low, as derived from a family of 58 proteins annotated as urocanases in the data banks. However, one well-embedded member of this family showed a significant deviation at the active center indicating an incorrect annotation.
Heritable disorders of hair
1987, Dermatologic Clinics
Changes in the quality and quantity of hair occur in a large number of hereditary syndromes. Because of their rarity and our lack of knowledge about their pathophysiology, no entirely satisfactory classification of these hair disorders exists. This review arbitrarily groups the heritable disorders of the hair into five classes: primary hair shaft disorders, alopecia without associated defects, ectodermal dysplasias, changes in hair color, and ectopic hair.
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A liver urocanase deficiency

Abstract

J Pediatr

Clin Chem Acta

Clin Chim Acta

Lancet

Clin Chim Acta

Clin Endocrinol Metab

A familial disturbance of histidine metabolism

N Engl J Med

Inborn errors of histidine metabolism

Pediatrics

Clinical and biochemical studies on two cases of histidinemia

Pediatrics

Histidinemia

Am J Dis Child