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Correlation resonance generated by coupled enzymatic processing.

ABSTRACT: A major challenge for systems biology is to deduce the molecular interactions that underlie correlations observed between concentrations of different intracellular molecules. Although direct explanations such as coupled transcription or direct protein-protein interactions are often considered, potential indirect sources of coupling have received much less attention. Here we show how correlations can arise generically from a posttranslational coupling mechanism involving the processing of multiple protein species by a common enzyme. By observing a connection between a stochastic model and a multiclass queue, we obtain a closed form expression for the steady-state distribution of the numbers of molecules of each protein species. Upon deriving explicit analytic expressions for moments and correlations associated with this distribution, we discover a striking phenomenon that we call correlation resonance: for small dilution rate, correlations peak near the balance-point where the total rate of influx of proteins into the system is equal to the maximum processing capacity of the enzyme. Given the limited number of many important catalytic molecules, our results may lead to new insights into the origin of correlated behavior on a global scale.

SUBMITTER: Mather WH

PROVIDER: S-EPMC2980735 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Correlation resonance generated by coupled enzymatic processing.

Mather William H WH Cookson Natalie A NA Hasty Jeff J Tsimring Lev S LS Williams Ruth J RJ

Biophysical journal 20101101 10

A major challenge for systems biology is to deduce the molecular interactions that underlie correlations observed between concentrations of different intracellular molecules. Although direct explanations such as coupled transcription or direct protein-protein interactions are often considered, potential indirect sources of coupling have received much less attention. Here we show how correlations can arise generically from a posttranslational coupling mechanism involving the processing of multipl ...[more]

PMID: 21081064

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Project description:The intraglomerular renin-angiotensin system (RAS) is linked to the pathogenesis of progressive glomerular diseases. Glomerular podocytes and mesangial cells play distinct roles in the metabolism of angiotensin (ANG) peptides. However, our understanding of the RAS enzymatic capacity of glomerular endothelial cells (GEnCs) remains incomplete. We explored the mechanisms of endogenous cleavage of ANG substrates in cultured human GEnCs (hGEnCs) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and isotope-labeled peptide quantification. Overall, hGEnCs metabolized ANG II at a significantly slower rate compared with podocytes, whereas the ANG I processing rate was comparable between glomerular cell types. ANG II was the most abundant fragment of ANG I, with lesser amount of ANG-(1-7) detected. Formation of ANG II from ANG I was largely abolished by an ANG-converting enzyme (ACE) inhibitor, whereas ANG-(1-7) formation was decreased by a prolylendopeptidase (PEP) inhibitor, but not by a neprilysin inhibitor. Cleavage of ANG II resulted in partial conversion to ANG-(1-7), a process that was attenuated by an ACE2 inhibitor, as well as by an inhibitor of PEP and prolylcarboxypeptidase. Further fragmentation of ANG-(1-7) to ANG-(1-5) was mediated by ACE. In addition, evidence of aminopeptidase N activity (APN) was demonstrated by detecting amelioration of conversion of ANG III to ANG IV by an APN inhibitor. While we failed to find expression or activity of aminopeptidase A, a modest activity attributable to aspartyl aminopeptidase was detected. Messenger RNA and gene expression of the implicated enzymes were confirmed. These results indicate that hGEnCs possess prominent ACE activity, but modest ANG II-metabolizing activity compared with that of podocytes. PEP, ACE2, prolylcarboxypeptidase, APN, and aspartyl aminopeptidase are also enzymes contained in hGEnCs that participate in membrane-bound ANG peptide cleavage. Injury to specific cell types within the glomeruli may alter the intrarenal RAS balance.

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Correlation resonance generated by coupled enzymatic processing.

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Correlation resonance generated by coupled enzymatic processing.

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