Membrane dipeptidases

An exopeptidase that can only degrade a dipeptide. Examples are carnosine dipeptidase I (MEROPS M20.006), which degrades carnosine (beta-Ala-His), and membrane dipeptidase (MEROPS Ml9.001), which is important in the catabolism of glutathione, degrading the dipeptides Cys-Gly. Dipeptidases are included in Enzyme Nomenclature sub-subclass 3.4.13. 

Rajotte D, Ruoslahti E. Membrane dipeptidase is the receptor for a lung-targeting peptide identified by in vivo phage display. J Biol Chem 1999 274 11593-11598. 

There are many dipeptidases [EC 3.4.13.x]. Cytosol nonspecific dipeptidase [EC 3.4.13.18] (also referred to as peptidase A, glycylglycine dipeptidase, glycylleucine dipeptidase, and A -)3-alanylarginine dipeptidase) catalyzes the hydrolysis of dipeptides. Membrane dipeptidase [EC 3.1.13.19] (also known as microsomal dipeptidase, renal dipeptidase, and dehydropeptidase I) is a zinc-dependent enzyme (a member of the peptidase family M19) that also catalyzes the hydrolysis of dipeptides. 

Walmsley AR, Hooper NM (2003), Glycosylation efficiency of Asn-Xaa-Thr sequons is independent of distance from the C-terminus in membrane dipeptidase, Glyco-... 

Discovery and development of imipenemycilastatin. Am.J. Med., 78.3-21. Keynan.S. etat (1990) Isolation and characterisation of the cDNA, sequence conservation, expression and processing in vitro. Biochew. 267,517-525. Keynan. S- ef a/. (1995) The renal membrane dipeptidase (dehydropeptase I) inhibitor, cilastatin. inhibits the bacterial metallo-b-lactamase en me CphA. Antimicrob. Agents Chemother.. 38,1629-1631. 

S. Movahedi and N. Hooper, Insulin stimulates the release of the glycosyl phosphatidylinositol-anchored membrane dipeptidase from 3T3-L1 adipocytes through the action of a phospholipase C, Biochem. J., 1997, 326, 531-537. 

A GPl-anchor may also allow a protein to be selectively released from the cell surface upon hydrolysis by a GPI-specific phospholipase (e.g., Pl-phospholipase C or GPl-phospholipase D). This has been shown to occur for certain GPI-anchored proteins in mammalian cell culture. One example is GPI-anchored membrane dipeptidase which is released from the adipocyte cell surface by a phospholipase C in response to insulin (S. Movahedi, 2000). Interestingly, other GPI-anchored proteins are not released, indicating a level of regulation in insulin-stimulated hydrolysis of GPI-anchored proteins. GPI-anchored molecules have also been shown to transfer between cells and stably insert in the external leaflet of the acceptor cell s plasma membrane (M.G. Low, 1998). The biological significance of this event is unclear however, the ability of GPI-anchored proteins to transfer between cells has implications for the expression of foreign proteins on the cell surface. 

Figure 3.8 Structural analysis of a post-translationally modified peptide by MALDI-MS/MS. Porcine membrane dipeptidase, a GPi-anchored glycoprotein, was in-gel-digested by trypsin. The C-terminal CPi-anchored peptide was recovered from the peptide mixture by hydrophilic interaction chromatography (HiLiC) and then analyzed...

I. A. Brewis, M. A. Ferguson, A. Mehlert, A. J. Turner N. M. Hooper. Structures of the glycosyl-phosphatidylinositol anchors of porcine and human renal membrane dipeptidase. Comprehensive structural studies on the porcine anchor and interspecies comparison of the glycan core structures. J Biol Chem, 1995, 270, 22946-22956. 

The intestinal mucosal peptidases are distributed in the brush border and cytosol of the absorptive cell. There are, however, distinct differences between the brush border and cytosolic peptidases [75], The tetrapeptidase activity is associated exclusively with the brush border enzyme. Furthermore, brush border peptidases exhibit more activity against tripeptides than dipeptides, whereas the cytosolic enzymes show greater activity against dipeptides. Studies have demonstrated that more than 50% of dipeptidase activity was detected in the cytosol [76] and just 10% in the brush border membrane [77]. The brush border enzymes include... 

Membrane alanyl aminopeptidase (microsomal aminopeptidase, amino-peptidase M, EC 3.4.11.2) and peptidyl-dipeptidase A (angiotensin I converting enzyme, EC 3.4.15.1) located in the vascular endothelium and smooth muscle cell surface modulate the levels of vasoactive peptides [23], One of the roles of membrane-bound enzymes is to switch off the action of peptides in the vicinity of the target or to prevent them from gaining access to a region containing receptors that are activated only by locally released peptides. 

This zinc-dependent enzyme [EC 3.4.15.1] (also known as dipeptidyl carboxypeptidase I, dipeptidyl-dipeptidase A, kininase II, peptidase P, and carboxycathepsin) catalyzes the release of a C-terminal dipeptide at a neutral pH. The enzyme will also act on bradykinin. The presence of prolyl residues in angiotensin I and in bradykinin results in only single dipeptides being released due to the activity of this enzyme, a protein which belongs to the peptidase M2 family. The enzyme is a glycoprotein, generally membrane-bound, that is chloride ion-dependent. 

Luminal and Membrane Metabolism of Peptides and Proteins. In meaningful studies on peptide and protein drug absorption in the small intestine, it is prerequisite to distinguish among cavital, membrane contact, and intracellular drug metabolism.Cavital metabolism takes place in the lumen of the small intestine by enzymes such as trypsin, chymotrypsin, carboxypepti-dase, and elastase, which are secreted by the pancreas. Membrane contact metabolism is carried out by aminopeptidases lo-calized on the brush border membrane. Intracellular metabolism occurs inside of the cells. The known intra-celluar enzymes are cytoplasmic peptidases, prolidase, dipeptidase, and tripeptidase.A more detailed dis-cussion of this topic is presented in section Intestinal Absorption Barriers, later. 

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