Intestinal Carbamoyl Phosphate Synthase I in Human and Rat: Expression During Development Shows Species Differences and Mosaic Expression in Duodenum of Both Species

Beers, Erik H. van; Rings, Edmond H. H. M.; Posthuma, George; Dingemanse, Maria A.; Taminiau, J. A.M.; Heymans, H. S. A.; Einerhand, Alexandra W. C.; Büller, Hans A.; Dekker, Jan

doi:10.1177/002215549804600212

Cited by 18 publications

(23 citation statements)

References 33 publications

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“…The strong correlation between crypt depth and CPS mRNA expression was in line with the fact that CPS mRNA is expressed exclusively by crypt enterocytes, whereas the protein is also found in villous enterocytes (Van Beers et al 1998). The time lag between the decrease in CPS mRNA and protein levels can also be explained by their different localization pattern along the crypt-villous axis.…”

Section: Discussionsupporting

confidence: 62%

Specific Responses in Rat Small Intestinal Epithelial mRNA Expression and Protein Levels During Chemotherapeutic Damage and Regeneration

Verburg

Renes

Nispen

et al. 2002

J Histochem Cytochem.

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S U M M A R YThe rapidly dividing small intestinal epithelium is very sensitive to the cytostatic drug methotrexate. We investigated the regulation of epithelial gene expression in rat jejunum during methotrexate-induced damage and regeneration. Ten differentiation markers were localized on tissue sections and quantified at mRNA and protein levels relative to control levels. We analyzed correlations in temporal expression patterns between markers. mRNA expression of enterocyte and goblet cell markers decreased significantly during damage for a specific period. Of these, sucrase-isomaltase ( Ϫ 62%) and CPS ( Ϫ 82%) were correlated. Correlations were also found between lactase ( Ϫ 76%) and SGLT1 ( Ϫ 77%) and between I-FABP ( Ϫ 52%) and L-FABP ( Ϫ 45%). Decreases in GLUT5 ( Ϫ 53%), MUC2 ( Ϫ 43%), and TFF3 ( Ϫ 54%) mRNAs occurred independently of any of the other markers. In contrast, lysozyme mRNA present in Paneth cells increased ( ϩ 76%). At the protein level, qualitative and quantitative changes were in agreement with mRNA expression, except for Muc2 ( ϩ 115%) and TFF3 ( ϩ 81%), which increased significantly during damage, following independent patterns. During regeneration, expression of each marker returned to control levels. The enhanced expression of cytoprotective molecules (Muc2, TFF3, lysozyme) during damage represents maintenance of goblet cell and Paneth cell functions, most likely to protect the epithelium. Decreased expression of enterocyte-specific markers represents decreased enterocyte function, of which fatty acid transporters were least affected.

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Section: Discussionsupporting

confidence: 62%

Specific Responses in Rat Small Intestinal Epithelial mRNA Expression and Protein Levels During Chemotherapeutic Damage and Regeneration

Verburg

Renes

Nispen

et al. 2002

J Histochem Cytochem.

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“…CPS-I is highly expressed in most of the small intestine during the entire lifespan in human and rat. Age-related increases in CPS-I mRNA levels have been demonstrated in humans between the embryonic period and 12 years (89).…”

Section: L-citrulline Metabolism Synthesismentioning

confidence: 99%

Therapeutic Use of Citrulline in Cardiovascular Disease

Romero

Platt

Caldwell

2006

Cardiovascular Drug Reviews

190

178

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L-citrulline is the natural precursor of L-arginine, substrate for nitric oxide synthase (NOS) in the production of NO. Supplemental administration L-arginine has been shown to be effective in improving NO production and cardiovascular function in cardiovascular diseases associated with endothelial dysfunction, such as hypertension, heart failure, atherosclerosis, diabetic vascular disease and ischemia-reperfusion injury, but the beneficial actions do not endure with chronic therapy. Substantial intestinal and hepatic metabolism of L-arginine to ornithine and urea by arginase makes oral delivery very ineffective. Additionally, all of these disease states as well as supplemental L-arginine enhance arginase expression and activity, thus reducing the effectiveness of L-arginine therapy. In contrast, L-citrulline is not metabolized in the intestine or liver and does not induce tissue arginase, but rather inhibits its activity. L-citrulline entering the kidney, vascular endothelium and other tissues can be readily converted to L-arginine, thus raising plasma and tissue levels of L-arginine and enhancing NO production. Supplemental L-citrulline has promise as a therapeutic adjunct in disease states associated with L-arginine deficiencies.

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“…introns [4][5][6], with 4,500 coding nucleotides, encodes a 1500-residue proenzyme [7] that is synthesized in hepatocytes and enterocytes [8,9], and which, upon internalization to the mitochondrial matrix, yields after cleavage of its N-terminal 38 amino acids, the mature 1,462-amino acid multidomain (Fig. 1A) CPS1 protein [10][11][12] [E.C.…”

Section: Introductionmentioning

confidence: 99%

Understanding carbamoyl phosphate synthetase (CPS1) deficiency by using the recombinantly purified human enzyme: Effects of CPS1 mutations that concentrate in a central domain of unknown function

Dı́ez-Fernández

Cervera

et al. 2014

Molecular Genetics and Metabolism

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Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is an inborn error of the urea cycle that is due to mutations in the CPS1 gene. In the first large repertory of mutations found in CPS1D, a small CPS1 domain of unknown function (called the UFSD) was found to host missense changes with high frequency, despite the fact that this domain does not host substrate-binding or catalytic machinery. We investigate here by in vitro expression studies using baculovirus/insect cells the reasons for the prominence of the UFSD in CPS1D, as well as the disease-causing roles and pathogenic mechanisms of the mutations affecting this domain. All but three of the 18 missense changes found thus far mapping in this domain in CPS1D patients drastically decreased the yield of pure CPS1, mainly because of decreased enzyme solubility, strongly suggesting misfolding as a major determinant of the mutations negative effects. In addition, the majority of the mutations also decreased from modestly to very drastically the specific activity of the fraction of the enzyme that remained soluble and that could be purified, apparently because they decreased V max . Substantial although not dramatic increases in K m values for the substrates or for N-acetyl-L-glutamate were observed for only five mutations.Similarly, important thermal stability decreases were observed for three mutations. The results indicate a disease-causing role for all the mutations, due in most cases to the combined effects of the low enzyme level and the decreased activity. Our data strongly support the value of the present expression system for ascertaining the disease-causing potential of CPS1 mutations, provided that the CPS1 yield is monitored. The observed effects of the mutations have been rationalized on the basis of an existing structural model of CPS1. This model shows that the UFSD, which is in the middle of the 1462-residue multidomain CPS1 protein, plays a key integrating role for creating the CPS1 multidomain architecture leading us to propose here a denomination of "Integrating 3 Domain" for this CPS1 region. The majority of these 18 mutations distort the interaction of this domain with other CPS1 domains, in many cases by causing improper folding of structural elements of the Integrating Domain that play key roles in these interactions.

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Intestinal Carbamoyl Phosphate Synthase I in Human and Rat: Expression During Development Shows Species Differences and Mosaic Expression in Duodenum of Both Species

Cited by 18 publications

References 33 publications

Specific Responses in Rat Small Intestinal Epithelial mRNA Expression and Protein Levels During Chemotherapeutic Damage and Regeneration

Specific Responses in Rat Small Intestinal Epithelial mRNA Expression and Protein Levels During Chemotherapeutic Damage and Regeneration

Therapeutic Use of Citrulline in Cardiovascular Disease

Understanding carbamoyl phosphate synthetase (CPS1) deficiency by using the recombinantly purified human enzyme: Effects of CPS1 mutations that concentrate in a central domain of unknown function

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