Ornithine Transcarbamylase – From Structure to Metabolism: An Update

Couchet, Morgane; Breuillard, C.; Corne, Christelle; Rendu, John; Morio, Béatrice; Schlattner, Uwe; Moinard, Christophe

doi:10.3389/fphys.2021.748249

Cited by 31 publications

(26 citation statements)

References 118 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: Resultssupporting

confidence: 90%

“…The region between residues 265 and 280 contains the conserved SMG loop, which may undergo a conformational change upon the binding of carbamoyl phosphate and ornithine that shields the active site of the enzyme. 34 It has been suggested that despite its conservation, most amino acid changes in the loop would not necessarily affect its function 35 and our results are consistent with this hypothesis. While OTC shows a general intolerance to amino acid substitutions, we expected that altering the amino acid at an active site of the enzyme would have a particularly high likelihood of impairing OTC function and therefore inhibiting growth in our assay.…”

Section: A High Proportion Of Amino Acid Substitutions Impair Otc Act...supporting

confidence: 90%

See 1 more Smart Citation

The functional impact of 1,570 SNP-accessible missense variants in humanOTC

Cromie

Tang

et al. 2022

Preprint

View full text Add to dashboard Cite

Deleterious mutations in the X-linked gene encoding ornithine transcarbamylase (OTC) cause the most common urea cycle disorder, OTC deficiency. This rare, but highly actionable disease can present with severe neonatal onset in males or with later onset in either sex. Neonatal onset patients appear normal at birth but rapidly develop hyperammonemia, which can progress to cerebral edema, coma and death, outcomes ameliorated by rapid diagnosis and treatment. Existing biochemical assays have limitations, including the sensitivity of the citrulline assays used in newborn screening panels. With prior knowledge of variant pathogenicity, DNA sequence-based diagnostics would provide an alternative screening method. Here, we develop a high throughput functional assay for human OTC and measure the impact of 1,570 variants, 84% of all SNP-accessible missense mutations. Our assay scores agree well with existing clinical significance calls, distinguishing known benign from pathogenic variants and variants with neonatal onset from late-onset disease presentation. Further, use of an intronless expression construct allows us to measure the impact of amino acid changes at splice sites independent of their effect on splicing, thereby separating the contribution of splicing and protein coding changes to aid the analysis of molecular mechanisms underlying pathogenicity. Finally, we assess the utility of our functional data on OTC variant curation by using the current ACMG/AMP guidelines to reclassify variants. Inclusion of our data as PS3/BS3 substantially improves variant interpretation. Thus, our dataset is of high clinical utility and illustrates the power of functional assays to inform interpretation of existing and novel genetic variation.

show abstract

Section: Resultssupporting

confidence: 90%

Section: A High Proportion Of Amino Acid Substitutions Impair Otc Act...supporting

confidence: 90%

The functional impact of 1,570 SNP-accessible missense variants in humanOTC

Cromie

Tang

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Interestingly, the expression of amino acid synthesis-related genes was significantly increased. These genes include glutamine synthesis-related gs (Eelen et al, 2018), cystathionine synthesis-related csb (Casique et al, 2013), proline synthesis-related aldh18a1 (Baumgartner et al, 2000), S-adenosylmethionine synthesis-related mata2 and L-citrulline-synthesis-related oct (Couchet et al, 2021). As a consequence, the increased amino acid synthesis and decreased amino acid catabolism in the SL12 group could be attributed to the increased whole-body protein and amino acid contents in larvae.…”

Section: Sl-enriched Diets Decreased Amino Acid Catabolismmentioning

confidence: 99%

Effects of Soybean Lecithin on Growth Performance, Intestine Morphology, and Liver Tissue Metabolism in Rock Bream (Oplegnathus fasciatus) Larvae

Tan

Zhang

et al. 2022

Front. Mar. Sci.

View full text Add to dashboard Cite

Investigations have demonstrated a strong and positive association between dietary intact phospholipid (PL) inclusion and aquatic larval growth, nevertheless, the precise molecular mechanism underlying PL inclusion on growth performance has not been well elucidated. This study aimed to investigate the effects of dietary soybean lecithin (SL) inclusion on growth performance, liver metabolism, resistance to hypoxia stress, and potential molecular mechanisms in rock bream (Oplegnathus fasciatus) larvae. Four types of equal-protein and equal-lipid content microdiets (MDs) were formulated with graded levels of SL to achieve phospholipid levels of (PLs, dry matter) 3.84% (SL0), 6.71% (SL4), 9.38% (SL8), and 12.21% (SL12). Rock bream larvae (25 days post-hatching) were fed the respective MDs for 30 days with three replicates. We found that dietary SL inclusion promoted growth performance, survival rate, and stress resistance to hypoxia stress. The increased dietary SL inclusion improved intestinal structure, as shown by the increased perimeter ratio, muscular thickness, and mucosal fold height of the mid-intestinal tissue. Moreover, a high SL inclusion diet (SL12) increased the activity of the key lipolysis-related enzyme (lipase [LP]) in liver tissue but decreased the activity of amino acid catabolism-related enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]). RNA sequencing results in liver tissue revealed that the SL12 diet increased the transcriptional level of fatty acid activation-related genes (acsl6 and acsbg2), phospholipid catabolism-related genes (acat2, lpin2, and crls), and amino acid synthesis-related genes (gs, csb, aldh18a1, and oct), but decreased the expression of amino acid catabolism-related gene gprt2. Notably, the SL12 diet significantly increased the expression of ribosome biogenesis-related genes (pes1, nop56, nop58, and rpf2) in liver tissue. The ribosome protein-related pathways were the most enriched pathways mapped in the GO database. Collectively, this study demonstrated the necessity of dietary SL for survival, growth performance, promotion of mid-intestinal morphology, and hypoxia stress during the rock bream larval stage. The SL-induced growth performance promotion was likely attributed to increasing nutrient acquisition by intestinal morphology improvement and to increasing SL catabolism and thereby sparing amino acids for protein synthesis.

show abstract

“…l ‐citrulline (CIT) is a nonessential amino acid synthesized in enterocytes from dietary l ‐arginine (ARG) and l ‐glutamine (GLN) using the ornithine carbamoyltransferase (OCT) enzyme 1 . CIT gets released into the portal vein and, as it is not taken up by the liver, reaches systemic circulation.…”

Section: Introductionmentioning

confidence: 99%

“…L-citrulline (CIT) is a nonessential amino acid synthesized in enterocytes from dietary L-arginine (ARG) and Lglutamine (GLN) using the ornithine carbamoyltransferase (OCT) enzyme. 1 CIT gets released into the portal vein and, as it is not taken up by the liver, reaches systemic circulation. Circulating CIT is then taken up by the kidneys and converted into ARG by argininosuccinate synthase and argininosuccinate lyase (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Regulation of citrulline synthesis in human enterocytes: Role of hypoxia and inflammation

et al. 2021

Self Cite

View full text Add to dashboard Cite

Intensive care unit patients and chronic airway inflammatory disease are characterized by chronic systemic hypoxia and inflammation inducing a decrease in nitric oxide release due to impaired L-arginine (ARG) homeostasis. As ARG is synthesized from circulating L-citrulline (CIT), an alteration of CIT production in small intestine by ornithine carbamoyltransferase could be involved. Here, we posit that hypoxia and/or inflammation has effects on ornithine carbamoyltransferase regulation in enterocytes. A duodenal explant incubation model was used. Biopsy specimens taken from 25 selected patients were incubated for 6 h in 4 groups: control, inflammation, hypoxia, and hypoxia + inflammation. At the end of the incubation period, we measured CIT concentration in culture media, ornithine carbamoyltransferase activity, ornithine carbamoyltransferase protein and gene expression, protein expression of enzymes involved in the CIT production pathway, and expression of energy status proteins. Inflammation and/or hypoxia conditions did not affect CIT production. Ornithine carbamoyltransferase activity was increased in hypoxia conditions (p = 0.023). Expression of enzymes implicated in the CIT crossroads pathway and enzymes reflecting energy status variation was not affected by inflammation and hypoxia. Data sets were pooled to evaluate the variability of the four quartiles for each parameter. CIT production was found to increase over the quartiles whereas other parameters remained stable. Our results showed that intestinal CIT production is preserved during inflammation and/or hypoxia, thus confirming the significance of this metabolic pathway. This suggests that the CIT deficiency observed in clinical hypercatabolic states could be a consequence of high utilization for ARG synthesis.

show abstract

Ornithine Transcarbamylase – From Structure to Metabolism: An Update

Cited by 31 publications

References 118 publications

The functional impact of 1,570 SNP-accessible missense variants in humanOTC

The functional impact of 1,570 SNP-accessible missense variants in humanOTC

Effects of Soybean Lecithin on Growth Performance, Intestine Morphology, and Liver Tissue Metabolism in Rock Bream (Oplegnathus fasciatus) Larvae

Regulation of citrulline synthesis in human enterocytes: Role of hypoxia and inflammation

Contact Info

Product

Resources

About