Progastriscin: Structure, Function, and Its Role in Tumor Progression

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
Journal of Molecular Cell Biology (Impact Factor: 6.77). 03/2010; 2(3):118-27. DOI: 10.1093/jmcb/mjq001
Source: PubMed

ABSTRACT Progastricsin (PGC) is a major seminal plasma protein having aspartyl proteinases-like activity and showing close sequence similarity to pepsins. PGC is also present as zymogen in gastric mucosa. In this article, we have reviewed all important features of PGC. Furthermore, we have compared all features of PGC with those of different aspartyl proteinases. The complete amino acid sequence of PGC reveals that it is composed of 374 residues (gastricsin moiety of 331 residues and the activation segment of 43 residues). The gene of human PGC is located at single locus on chromosome 6, whereas the human pepsinogen genetic locus is polymorphic and codes for at least three distinct polypeptide sequences on chromosome 11. The major useful function of PGC includes production of pro-antimicrobial substance in seminal plasma. The crystal structure of human PGC is known, which shows that it is quite similar to that of porcine pepsinogen. The tertiary structure of PGC is comprised of commonly bilobal structure with a large active-site cleft between the lobes. Two aspartate residues in the center of the cleft, namely Asp32 and Asp215, function as catalytic residues. The sequence and structural features of PGC indicate that it is diverged from its pepsinogen ancestor in the early phase of the evolution of gastric aspartyl proteinases. Our detailed review of PGC structure, function and activation mechanism will also be of interest to cancer biologists as well as gastroenterologists.

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    • "There are two major cleavage sites in human PGC, one located between pPhe26 and pLeu27 and the second located at the last residue of the prosegment pLeu43 and the first residue of the enzyme moiety Ser1 [1], [3], [25]. In a neutral pH the prosegment is coupled to the enzyme moiety by electrostatic interactions and hydrogen-bonds, pLys37, pTyr38 and Tyr9 (Fig. 1 green boxes) bind to the catalytic aspartates (Fig. 1 black boxes “+”) [1], [26], [27], [28] In an acidic pH environment acidic residues in the enzyme moiety become protonated disrupting electrostatic interactions with the prosegment (which has a basic character), releasing the prosegment for proteolytic cleavage and enzyme activation [3], [29], [30]. In fish pepsinogens a deletion of several residues in the prosegment is observed (Fig. 1 activation segment, lower black bar) leads to a decrease in the number of basic residues in the prosegment, and given the PI values for each enzyme region (Table 1), we deduced that the activation of fish pepsinogens occurs in conditions that are comparatively more alkaline. "
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    ABSTRACT: Aspartic proteases comprise a large group of enzymes involved in peptide proteolysis. This collection includes prominent enzymes globally categorized as pepsins, which are derived from pepsinogen precursors. Pepsins are involved in gastric digestion, a hallmark of vertebrate physiology. An important member among the pepsinogens is pepsinogen C (Pgc). A particular aspect of Pgc is its apparent single copy status, which contrasts with the numerous gene copies found for example in pepsinogen A (Pga). Although gene sequences with similarity to Pgc have been described in some vertebrate groups, no exhaustive evolutionary framework has been considered so far. By combining phylogenetics and genomic analysis, we find an unexpected Pgc diversity in the vertebrate sub-phylum. We were able to reconstruct gene duplication timings relative to the divergence of major vertebrate clades. Before tetrapod divergence, a single Pgc gene tandemly expanded to produce two gene lineages (Pgbc and Pgc2). These have been differentially retained in various classes. Accordingly, we find Pgc2 in sauropsids, amphibians and marsupials, but not in eutherian mammals. Pgbc was retained in amphibians, but duplicated in the ancestor of amniotes giving rise to Pgb and Pgc1. The latter was retained in mammals and probably in reptiles and marsupials but not in birds. Pgb was kept in all of the amniote clade with independent episodes of loss in some mammalian species. Lineage specific expansions of Pgc2 and Pgbc have also occurred in marsupials and amphibians respectively. We find that teleost and tetrapod Pgc genes reside in distinct genomic regions hinting at a possible translocation. We conclude that the repertoire of Pgc genes is larger than previously reported, and that tandem duplications have modelled the history of Pgc genes. We hypothesize that gene expansion lead to functional divergence in tetrapods, coincident with the invasion of terrestrial habitats.
    PLoS ONE 03/2012; 7(3):e32852. DOI:10.1371/journal.pone.0032852 · 3.23 Impact Factor
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    ABSTRACT: Pepsinogens are precursors of pepsins, which are gastric digestive proteinases that degrade food proteins into peptides. In the study reported here, the cDNA and its corresponding genomic DNA of the golden mandarin fish (Siniperca scherzeri, Perciformes) pepsinogen C (PGC) were cloned and sequenced. The golden mandarin fish PGC gene was deduced to have nine exons and eight introns, a structure similar to the PGCs of other vertebrates. The full-length cDNA was found to contain a 37-bp 5′-untranslated region, a 1,164-bp open reading frame, and a 304-bp 3′-untranslated region and the PGC protein to consist of a signal peptide, an activation segment, and a pepsin moiety. A sequence analysis revealed that pairwise sequence similarities of PGC proteins are around 70% between golden mandarin fish and other vertebrate groups, and around 90% within the fish group. A comparison of vertebrate PGC protein sequences revealed two motifs. One was in the activation segment that occurred only in the mammal and avian PGCs, suggesting that PGCs active in homeotherms (mammal and avian) have different activation mechanisms than those in poikilotherms (amphibian and fish). The second was in the pepsin moiety that occurred only in fish, suggesting the primitive position of fish among vertebrates. PGC mRNA is mainly expressed in the stomach and esophagus and at much lower levels in the skin and muscle. Taken together with results reported from other studies, the results reported here will lead to a better understanding of the molecular mechanisms of fish digestive physiology and the evolution of fish pepsinogen genes. KeywordsGolden mandarin fish-Molecular characterization-Pepsinogen C-Tissue expression
    Fisheries Science 09/2010; 76(5):819-826. DOI:10.1007/s12562-010-0275-x · 0.88 Impact Factor
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    ABSTRACT: The digestive system works in concert with the other organ systems of the body, and with the external environment, in particular ingested material and microorganisms. The pathway from the point of ingestion to the point of excretion is long and tortuous, and is made up of dozens of niches with specialized physiologic roles and constellations of proteases. In each of these niches, there is a characteristic array of molecules from the lumen to the surface of the cells lining the alimentary tract (Hopfer 2011). The cellular level is a heterogeneous mosaic of resident and transient cells with special functions and arrays of proteases. This chapter will focus on the mammalian proteases found in the lumen and on the cell surface of the alimentary tract, both membrane-bound and secreted proteases. The proteases of the intestinal bacteria, mainly in the lower intestine, are dealt with in separate chapters, but structures and products of bacteria will be addressed as substrates and as factors that affect protease expression and activity. Similarly, the proteases of immune cells, which are transient members of the digestive system, are dealt with separately in other chapters, but their roles in the alimentary tract are inextricably enmeshed in normal physiologic processes of digestion and pathologic responses to injury. Accordingly, this review of proteases in the digestive system will focus on the human system beginning anatomically at the oral cavity, and proceed to the esophagus, stomach, and the niches of the intestinal tract, ending with the colon. Representative protease functions in intestinal pathobiology are discussed in the anatomical sections and in separate sections at the end of the chapter. There is detailed information on the many proteases mentioned in this chapter in the Handbook of Proteolytic Enzymes, second Edition (Barrett et al. 2004) and the third Edition (Rawlings and Salvesen 2013), and in the MEROPs database (http:// www. merops. sanger. ac. uk).
    Proteases Structure and Function, DOI 10.1007/978-3-7091-0885-7_11 edited by K. Brix and W. Stoecker, 11/2013: chapter 11; Springer Verlag.
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