PEPD: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
m (Robot: Automated text replacement (-{{WikiDoc Cardiology Network Infobox}} +, -<references /> +{{reflist|2}}, -{{reflist}} +{{reflist|2}}))
 
m (Bot: HTTP→HTTPS (v470))
Line 1: Line 1:
{{about|Human Gene|the Pain Disorder|Paroxysmal extreme pain disorder}}
{{about|human gene PEPD|the pain disorder|Paroxysmal extreme pain disorder}}
<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''Xaa-Pro dipeptidase''', also known as '''prolidase''', is an [[enzyme]] that in humans is encoded by the ''PEPD'' [[gene]].<ref name="pmid2925654">{{cite journal | vauthors = Endo F, Tanoue A, Nakai H, Hata A, Indo Y, Titani K, Matsuda I | title = Primary structure and gene localization of human prolidase | journal = The Journal of Biological Chemistry | volume = 264 | issue = 8 | pages = 4476–81 | date = Mar 1989 | pmid = 2925654 | pmc =  | doi =  }}</ref><ref name="pmid1972707">{{cite journal | vauthors = Tanoue A, Endo F, Matsuda I | title = Structural organization of the gene for human prolidase (peptidase D) and demonstration of a partial gene deletion in a patient with prolidase deficiency | journal = The Journal of Biological Chemistry | volume = 265 | issue = 19 | pages = 11306–11 | date = Jul 1990 | pmid = 1972707 | pmc = | doi = }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PEPD peptidase D| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5184| accessdate = }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image = PBB_Protein_PEPD_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2iw2.
| PDB = {{PDB2|2iw2}}, {{PDB2|2okn}}
| Name = Peptidase D
| HGNCid = 8840
| Symbol = PEPD
| AltSymbols =; MGC10905; PROLIDASE
| OMIM = 170100
| ECnumber = 
| Homologene = 239
| MGIid = 97542
| GeneAtlas_image1 = PBB_GE_PEPD_202108_at_tn.png
| Function = {{GNF_GO|id=GO:0004251 |text = X-Pro dipeptidase activity}} {{GNF_GO|id=GO:0008472 |text = metallocarboxypeptidase D activity}} {{GNF_GO|id=GO:0030145 |text = manganese ion binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
| Component =
| Process = {{GNF_GO|id=GO:0006508 |text = proteolysis}} {{GNF_GO|id=GO:0006520 |text = amino acid metabolic process}} {{GNF_GO|id=GO:0030574 |text = collagen catabolic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5184
    | Hs_Ensembl = ENSG00000124299
    | Hs_RefseqProtein = NP_000276
    | Hs_RefseqmRNA = NM_000285
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 19
    | Hs_GenLoc_start = 38569705
    | Hs_GenLoc_end = 38704540
    | Hs_Uniprot = P12955
    | Mm_EntrezGene = 18624
    | Mm_Ensembl = ENSMUSG00000063931
    | Mm_RefseqmRNA = NM_008820
    | Mm_RefseqProtein = NP_032846
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 7
    | Mm_GenLoc_start = 34621153
    | Mm_GenLoc_end = 34753468
    | Mm_Uniprot = Q11136
  }}
}}
'''Peptidase D''', also known as '''PEPD''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: PEPD peptidase D| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5184| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
Xaa-Pro dipeptidase is a cytosolic [[dipeptidase]] that hydrolyzes dipeptides with [[proline]] or [[hydroxyproline]] at the carboxy terminus (but not Pro-Pro). It is important in collagen metabolism because of the high levels of [[imino acid]]s.<ref name="entrez" /> Mutations at the PEPD locus cause [[prolidase deficiency]]. This is characterised by Iminodipeptidurea, [[skin ulcers]], [[mental retardation]] and recurrent infections.
{{PBB_Summary
| section_title =
| summary_text = Xaa-Pro dipeptidase is a cytosolic dipeptidase that hydrolyzes dipeptides with proline or hydroxyproline at the carboxy terminus (but not Pro-Pro). It is important in collagen metabolism because of the high levels of aminoacids.<ref name="entrez">{{cite web | title = Entrez Gene: PEPD peptidase D| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5184| accessdate = }}</ref>
}}


==References==
== Structure ==
{{reflist|2}}
 
==Further reading==
Prolidases fall under a subclass of [[metallopeptidase]]s that involve binuclear [[active site]] [[metal cluster]]s.<ref name="Guss 2004">{{cite journal | vauthors = Maher MJ, Ghosh M, Grunden AM, Menon AL, Adams MW, Freeman HC, Guss JM | title = Structure of the prolidase from Pyrococcus furiosus | journal = Biochemistry | volume = 43 | issue = 10 | pages = 2771–83 | date = Mar 2004 | pmid = 15005612 | doi = 10.1021/bi0356451 }}</ref> This metal cluster facilitates [[catalysis]] by serving as a [[substrate (chemistry)|substrate]] [[binding site]], activating [[nucleophile]]s, and stabilizing the [[transition state]]. Furthermore, prolidases are classified under a smaller family called “pita-bread” enzymes, which cleave [[amide|amido-]], [[imine|imido-]], and [[amidine|amidino-]] containing bonds.<ref name="Matthews_2002">{{cite journal | vauthors = Lowther WT, Matthews BW | title = Metalloaminopeptidases: common functional themes in disparate structural surroundings | journal = Chemical Reviews | volume = 102 | issue = 12 | pages = 4581–608 | date = Dec 2002 | pmid = 12475202 | doi = 10.1021/cr0101757 }}</ref> The “pita-bread” fold, containing a metal center flanked by two well-defined substrate binding pockets enabled prolidase to specifically cleave between any non-proline [[amino acid]] and proline.
{{refbegin | 2}}
 
{{PBB_Further_reading
[[File:Prolidase cleavage of peptide to yield alanine and proline.png|Prolidase cleavage of peptide to yield alanine and proline]]
| citations =  
 
*{{cite journal  | author=Tanoue A, Endo F, Matsuda I |title=Structural organization of the gene for human prolidase (peptidase D) and demonstration of a partial gene deletion in a patient with prolidase deficiency. |journal=J. Biol. Chem. |volume=265 |issue= 19 |pages= 11306-11 |year= 1990 |pmid= 1972707 |doi= }}
The first ever solved structure of prolidase came from the [[hyperthermophilic]] [[archaeon]] [[Pyrococcus furiosus]] (Pfprol).<ref name="Guss 2004"/> This dimer has a crystal structure shows two approximately symmetrical [[monomer]]s that both have an [[N-terminus|N-terminal domain]], made up of a six-stranded mixed β-sheet flanked by five [[alpha helix|α-helices]], a helical linker, and [[C-terminus|C-terminal domain]], consisting of a mixed six-stranded [[Beta sheet|β-sheet]] flanked by four α-helices. The curved β-sheet of Domain II has a “pita-bread” fold. The active site lies on the inner surface of the β-sheet of Domain II, with a notable dinuclear [[cobalt|Co]] cluster anchored by the side chains of two [[aspartate]] [[residue (chemistry)|residues]] (Asp209 and Asp220), two [[glutamate]] residues (Glu313 and Glu327), and a [[histidine]] residue (His284). [[Carboxylate]] groups of aspartate and [[glutamine]] residues serve as bridges between the two Co atoms. In the [[crystallization]] process, the Co atoms are replaced with [[zinc|Zn]], which hinders enzymatic activity.
*{{cite journal | author=Tanoue A, Endo F, Kitano A, Matsuda I |title=A single nucleotide change in the prolidase gene in fibroblasts from two patients with polypeptide positive prolidase deficiency. Expression of the mutant enzyme in NIH 3T3 cells. |journal=J. Clin. Invest. |volume=86 |issue= 1 |pages= 351-5 |year= 1990 |pmid= 2365824 |doi=  }}
 
*{{cite journal  | author=Boright AP, Scriver CR, Lancaster GA, Choy F |title=Prolidase deficiency: biochemical classification of alleles. |journal=Am. J. Hum. Genet. |volume=44 |issue= 5 |pages= 731-40 |year= 1989 |pmid= 2705457 |doi=  }}
Unlike Pfprol, the structure of the human variant remains poorly understood. Sequence [[homology (biology)|homology]] between human and Pfprol yield only 25% identity and 43% similarity.<ref name="Forlino 2008">{{cite journal | vauthors = Lupi A, Tenni R, Rossi A, Cetta G, Forlino A | title = Human prolidase and prolidase deficiency: an overview on the characterization of the enzyme involved in proline recycling and on the effects of its mutations | journal = Amino Acids | volume = 35 | issue = 4 | pages = 739–52 | date = Nov 2008 | pmid = 18340504 | doi = 10.1007/s00726-008-0055-4 }}</ref> The two available structures of human prolidase available on the [[Protein Data Bank]] are [[homodimers]] contain either [[sodium|Na]] or [[manganese|Mn]], which bind to similar amino acids as those in Pfprol: Glu412 (Glu313 in Pfprol), binds to the first ion, Asp276 (Asp209 in Pfprol) binds to the second ion, and Asp287 and Glu452 bind to both (Asp220 and Glu327 in Pfprol).
*{{cite journal  | author=Friedrich U, Brunner H, Smeets D, ''et al.'' |title=Three-point linkage analysis employing C3 and 19cen markers assigns the myotonic dystrophy gene to 19q. |journal=Hum. Genet. |volume=75 |issue= 3 |pages= 291-3 |year= 1987 |pmid= 2881880 |doi=  }}
 
*{{cite journal  | author=Endo F, Tanoue A, Nakai H, ''et al.'' |title=Primary structure and gene localization of human prolidase. |journal=J. Biol. Chem. |volume=264 |issue= 8 |pages= 4476-81 |year= 1989 |pmid= 2925654 |doi= }}
[[File:Pfprol active site.png|thumb|Asp209, Asp220, Glu313, Glu327, and His284 make up the active site of prolidase from [[Pyrococcus furiosus]] (1PV9). The zinc ions are bridged by the carboxylate groups of aspartate and glutamine residues. Bond lengths between the zinc ions and carboxylate groups of the amino acids are also indicated.]]
*{{cite journal  | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171-4 |year= 1994 |pmid= 8125298 |doi= }}
 
*{{cite journal | author=Ledoux P, Scriver C, Hechtman P |title=Four novel PEPD alleles causing prolidase deficiency. |journal=Am. J. Hum. Genet. |volume=54 |issue= 6 |pages= 1014-21 |year= 1994 |pmid= 8198124 |doi= }}
== Function ==
*{{cite journal  | author=Ledoux P, Scriver CR, Hechtman P |title=Expression and molecular analysis of mutations in prolidase deficiency. |journal=Am. J. Hum. Genet. |volume=59 |issue= 5 |pages= 1035-9 |year= 1996 |pmid= 8900231 |doi= }}
 
*{{cite journal  | author=Pałka JA |title=The role of prolidase as an enzyme participating in the metabolism of collagen. |journal=Rocz. Akad. Med. Bialymst. |volume=41 |issue= 2 |pages= 149-60 |year= 1997 |pmid= 9020526 |doi= }}
Due to proline’s cyclic structure, only few [[peptidase]]s could cleave the bond between proline and other amino acids.<ref name="Grunden 2012">{{cite journal | vauthors = Kitchener RL, Grunden AM | title = Prolidase function in proline metabolism and its medical and biotechnological applications | journal = Journal of Applied Microbiology | volume = 113 | issue = 2 | pages = 233–47 | date = Aug 2012 | pmid = 22512465 | doi = 10.1111/j.1365-2672.2012.05310.x }}</ref> Along with [[prolinase]], prolidase are the only known enzymes that can break down dipeptides to yield free proline. Prolidase serve to hydrolyze both dietary and [[endogenous]] Xaa-Pro dipeptides. More specifically, it is essential in catalyzing the last step of the degradation of procollagen, [[collagen]], and other proline-containing peptides into free amino acids to be used for cellular growth.<ref name="Phang 2008">{{cite journal | vauthors = Surazynski A, Miltyk W, Palka J, Phang JM | title = Prolidase-dependent regulation of collagen biosynthesis | journal = Amino Acids | volume = 35 | issue = 4 | pages = 731–8 | date = Nov 2008 | pmid = 18320291 | doi = 10.1007/s00726-008-0051-8 }}</ref> Additionally, it also participates in the process of recycling proline from Xaa-Pro dipeptides for collagen resynthesis. Proline and hydroyxyproline make up a quarter of the amino acid residues in collegen, which is the most abundant protein in the body by mass and plays an important role in maintaining [[connective tissue]] in the body.<ref name="Phang 2008"/><ref name="Liu 2008">{{cite journal | vauthors = Phang JM, Donald SP, Pandhare J, Liu Y | title = The metabolism of proline, a stress substrate, modulates carcinogenic pathways | journal = Amino Acids | volume = 35 | issue = 4 | pages = 681–90 | date = Nov 2008 | pmid = 18401543 | doi = 10.1007/s00726-008-0063-4 }}</ref>
*{{cite journal | author=Palka JA, Phang JM |title=Prolidase activity in fibroblasts is regulated by interaction of extracellular matrix with cell surface integrin receptors. |journal=J. Cell. Biochem. |volume=67 |issue= 2 |pages= 166-75 |year= 1997 |pmid= 9328822 |doi= }}
 
*{{cite journal  | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149-56 |year= 1997 |pmid= 9373149 |doi=  }}
==Mechanism==
*{{cite journal  | author=Muszyńska A, Pałka J, Gorodkiewicz E |title=The mechanism of daunorubicin-induced inhibition of prolidase activity in human skin fibroblasts and its implication to impaired collagen biosynthesis. |journal=Exp. Toxicol. Pathol. |volume=52 |issue= 2 |pages= 149-55 |year= 2000 |pmid= 10965990 |doi=  }}
 
*{{cite journal | author=Surazyński A, Pałka J |title=FAK-independent regulation of prolidase activity and collagen biosynthesis in MCF-7 cells. |journal=Folia Histochem. Cytobiol. |volume=39 Suppl 2 |issue= |pages= 212-3 |year= 2002 |pmid= 11820613 |doi= }}
The mechanism for prolidase catalytic activity remains largely uncharacterized.<ref name="Guss 2006">{{cite journal | vauthors = Graham SC, Lilley PE, Lee M, Schaeffer PM, Kralicek AV, Dixon NE, Guss JM | title = Kinetic and crystallographic analysis of mutant Escherichia coli aminopeptidase P: insights into substrate recognition and the mechanism of catalysis | journal = Biochemistry | volume = 45 | issue = 3 | pages = 964–75 | date = Jan 2006 | pmid = 16411772 | doi = 10.1021/bi0518904 }}</ref> However, biochemical and structural analyses of [[aminopeptidase]] (APPro), [[methionine aminopeptidase]] (MetAP), and prolidase, all members of the “pita-bread” [[metalloenzyme]]s, suggest that they share a common mechanism scheme.<ref name="Matthews_2002"/> The main difference arises in the location of the [[carbonyl]] oxygen atom of the [[scissile bond|scissile peptide bond]].
*{{cite journal | author=Harris RA, Yang A, Stein RC, ''et al.'' |title=Cluster analysis of an extensive human breast cancer cell line protein expression map database. |journal=Proteomics |volume=2 |issue= 2 |pages= 212-23 |year= 2002 |pmid= 11840567 |doi= }}
 
*{{cite journal  | author=Forlino A, Lupi A, Vaghi P, ''et al.'' |title=Mutation analysis of five new patients affected by prolidase deficiency: the lack of enzyme activity causes necrosis-like cell death in cultured fibroblasts. |journal=Hum. Genet. |volume=111 |issue= 4-5 |pages= 314-22 |year= 2002 |pmid= 12384772 |doi= 10.1007/s00439-002-0792-5 }}
[[File:Proposed mechanism scheme for metal-dependent "pita-bread" enzyme with eMetAP residue numbering.png|thumb|Proposed mechanism scheme for metal-dependent "pita-bread" enzyme with eMetAP residue numbering.<ref name="Matthews_2002"/>]]
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
 
*{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
The following mechanism shows a proposed scheme for a metal-dependent “pita-bread” enzyme with residue numbering corresponding to those found in methionine aminopeptidase from [[E coli|E. coli]].<ref name="Matthews_2002"/> As shown in Intermediate I of the figure, three potential [[acidic]] amino acid residues interact with the N-terminus of the substrate in a fashion that is yet to be determined. The carbonyl and amide groups of the scissile peptide bond interact with the first metal ion, M1, in addition to His178 and His79, respectively. M1 and Glu204 activate a water molecule to prepare it [[nucleophilic attack]] at the carbonyl carbon of the scissile peptide bond. Then, the [[Tetrahedral molecular geometry|tetrahedral]] [[Reaction intermediate|intermediate]] (Intermediate II) becomes stabilized from interactions with M1 and His178. Lastly, Glu204 donates a [[proton]] to the amine of the leaving [[peptide]] (P1’). This leads to the breakdown of the intermediate (Intermediate III), which retains its interactions with M1 and His178.
*{{cite journal | author=Beausoleil SA, Jedrychowski M, Schwartz D, ''et al.'' |title=Large-scale characterization of HeLa cell nuclear phosphoproteins. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 33 |pages= 12130-5 |year= 2004 |pmid= 15302935 |doi= 10.1073/pnas.0404720101 }}
 
*{{cite journal | author=Lupi A, De Riso A, Torre SD, ''et al.'' |title=Characterization of a new PEPD allele causing prolidase deficiency in two unrelated patients: natural-occurrent mutations as a tool to investigate structure-function relationship. |journal=J. Hum. Genet. |volume=49 |issue= 9 |pages= 500-6 |year= 2004 |pmid= 15309682 |doi= 10.1007/s10038-004-0180-1 }}
==Regulation==
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
 
}}
[[Posttranslational modification|Post-translational modifications]] of prolidase regulate its enzymatic abilities. [[Phosphorylation]] of prolidase has been shown to increase its activity while [[dephosphorylation]] leads to a decrease in enzyme activity.<ref name="Wolczynski 2001">{{cite journal | vauthors = Surazyński A, Pałka J, Wołczyński S | title = Phosphorylation of prolidase increases the enzyme activity | journal = Molecular and Cellular Biochemistry | volume = 220 | issue = 1-2 | pages = 95–101 | date = Apr 2001 | pmid = 11451388 | doi=10.1023/a:1010849100540}}</ref> Analysis of known [[consensus sequence]] required for [[serine]]/[[threonine]] phosphorylation revealed that prolidase contains at least three potential sites for serine/threonine phosphorylation. Nitric oxide, both [[exogeny|exogenously]] acquired and [[Endogeny (biology)|endogenously]] generated, was shown to increase prolidase activity in a time- and [[Dose–response relationship|dose-dependent]] manner via phosphorylation at these serine and threonine sites.<ref name="Phang 2005">{{cite journal | vauthors = Surazynski A, Liu Y, Miltyk W, Phang JM | title = Nitric oxide regulates prolidase activity by serine/threonine phosphorylation | journal = Journal of Cellular Biochemistry | volume = 96 | issue = 5 | pages = 1086–94 | date = Dec 2005 | pmid = 16167338 | doi = 10.1002/jcb.20631 }}</ref> Additionally, prolidase may also be regulated at [[tyrosine]] phosphorylation sites, which are mediated by [[PTK2|FAK]] and [[MAPK]] [[Signal transduction|signaling pathways]].<ref name="Wolczynski 2001"/>
 
==Disease relevance==
 
Deficiency in prolidase leads to a rare, severe [[Dominance (genetics)|autosomal recessive disorder]] ([[prolidase deficiency]]) that causes many chronic, debilitating health conditions in humans.<ref name="Iadarola 2006">{{cite journal | vauthors = Viglio S, Annovazzi L, Conti B, Genta I, Perugini P, Zanone C, Casado B, Cetta G, Iadarola P | title = The role of emerging techniques in the investigation of prolidase deficiency: from diagnosis to the development of a possible therapeutical approach | journal = Journal of Chromatography B | volume = 832 | issue = 1 | pages = 1–8 | date = Feb 2006 | pmid = 16434239 | doi = 10.1016/j.jchromb.2005.12.049 }}</ref> These [[Phenotype|phenotypical]] symptoms vary and may include [[skin ulcer]]ations, [[mental retardation]], [[splenomegaly]], recurrent [[infections]], [[photosensitivity]], [[hyperkeratosis]], and unusual facial appearance. Furthermore, prolidase activity was found to be abnormal compared to healthy levels in various medical conditions including but limited to: [[bipolar disorder]], [[breast cancer]], [[endometrial cancer]], [[keloid scar]] formation, [[erectile dysfunction]], [[liver disease]], [[lung cancer]], [[hypertension]], [[melanoma]], and [[chronic pancreatitis]].<ref name="Grunden 2012"/> In some cancers with increased levels of prolidase activity, such as melanoma, the differential expression of prolidase and its substrate specificity for dipeptides with proline at the [[carboxyl]] end suggests the potential of prolidase in becoming a viable, selective [[endogenous]] enzyme target for proline [[prodrugs]].<ref name="Amidon 2005">{{cite journal | vauthors = Mittal S, Song X, Vig BS, Landowski CP, Kim I, Hilfinger JM, Amidon GL | title = Prolidase, a potential enzyme target for melanoma: design of proline-containing dipeptide-like prodrugs | journal = Molecular Pharmaceutics | volume = 2 | issue = 1 | pages = 37–46 | year = 2005 | pmid = 15804176 | doi = 10.1021/mp049922p }}</ref> [[Serum (blood)|Serum]] prolidase enzyme activity is also currently being explored as a possible, reliable [[biomarker|marker]] for diseases including [[chronic hepatitis B]] and [[liver fibrosis]].<ref name="Tekin 2014">{{cite journal | vauthors = Şen V, Uluca Ü, Ece A, Kaplan İ, Bozkurt F, Aktar F, Bağlı S, Tekin R | title = Serum prolidase activity and oxidant-antioxidant status in children with chronic hepatitis B virus infection | journal = Italian Journal of Pediatrics | volume = 40 | issue = 1 | pages = 95 | date = Nov 2014 | pmid = 25425101 | pmc = 4247636 | doi = 10.1186/s13052-014-0095-1 }}</ref><ref name="Unlu 2013">{{cite journal | vauthors = Duygu F, Aksoy N, Cicek AC, Butun I, Unlu S | title = Does prolidase indicate worsening of hepatitis B infection? | journal = Journal of Clinical Laboratory Analysis | volume = 27 | issue = 5 | pages = 398–401 | date = Sep 2013 | pmid = 24038226 | doi = 10.1002/jcla.21617 }}</ref><ref name="Pillay 2014">{{cite journal | vauthors = Stanfliet JC, Locketz M, Berman P, Pillay TS | title = Evaluation of the utility of serum prolidase as a marker for liver fibrosis | journal = Journal of Clinical Laboratory Analysis | volume = 29 | issue = 3 | pages = 208–13 | date = May 2015 | pmid = 24798655 | doi = 10.1002/jcla.21752 }}</ref>
 
==Other applications==
 
[[Decontamination]]: Prolidase from the hyperthermophilic archaeon Pyrococcus furiosus (Pfprol) shows potential for application in decontamination of [[Organophosphorus compound|organophosphorus]] [[nerve agent]]s in [[Chemical weapon|chemical warfare agents]].<ref name="Grunden 2010">{{cite journal | vauthors = Theriot CM, Du X, Tove SR, Grunden AM | title = Improving the catalytic activity of hyperthermophilic Pyrococcus prolidases for detoxification of organophosphorus nerve agents over a broad range of temperatures | journal = Applied Microbiology and Biotechnology | volume = 87 | issue = 5 | pages = 1715–26 | date = Aug 2010 | pmid = 20422176 | doi = 10.1007/s00253-010-2614-3 }}</ref> Additionally, prolidase could also serve to detect [[fluorine]]-containing organophosphorus [[neurotoxin]]s, like the G-type chemical warfare agents, and could [[Receptor antagonist|antagonize]] organophosphorous [[Organophosphate poisoning|intoxication]] and protect against the effects of [[diisopropylfluorophosphate]] when [[Capsule (pharmacy)|encapsulated]] in [[liposome]]s.<ref name="Wild 2001">{{cite journal | last1 = Simonian | first1 = A. L. | last2 = Grimsley | first2 = J. K. | last3 = Flounders | first3 = A. W. | last4 = Schoeniger | first4 = J. S. | last5 = Cheng | first5 = T. C. | last6 = Defrank | first6 = J. J. | last7 = Wild | first7 = J. R. | title = Enzyme-based biosensor for the direct detection of fluorine-containing organophosphates | journal = Analytica Chimica Acta | volume = 442 | pages = 15–23 | year = 2001 | doi = 10.1016/S0003-2670(01)01131-X | name-list-format = vanc }}</ref><ref name="Way 2000">{{cite journal | vauthors = Petrikovics I, Cheng TC, Papahadjopoulos D, Hong K, Yin R, DeFrank JJ, Jaing J, Song ZH, McGuinn WD, Sylvester D, Pei L, Madec J, Tamulinas C, Jaszberenyi JC, Barcza T, Way JL | title = Long circulating liposomes encapsulating organophosphorus acid anhydrolase in diisopropylfluorophosphate antagonism | journal = Toxicological Sciences | volume = 57 | issue = 1 | pages = 16–21 | date = Sep 2000 | pmid = 10966507 | doi = 10.1093/toxsci/57.1.16 }}</ref>
 
== Model organisms ==
 
[[Model organism]]s have been used in the study of PEPD function. A conditional [[knockout mouse]] line called ''Pepd<sup>tm1a(KOMP)Wtsi</sup>'' was generated at the [[Wellcome Trust Sanger Institute]].<ref name="mgp_reference">{{cite journal |title=The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice |author=Gerdin AK |year=2010 |journal=Acta Ophthalmologica|volume=88 |pages=925–7|doi=10.1111/j.1755-3768.2010.4142.x }}</ref> Male and female animals underwent a standardized [[phenotypic screen]]<ref name="IMPCsearch_ref">{{cite web |url=http://www.mousephenotype.org/data/search?q=Pepd#fq=*:*&facet=gene |title=International Mouse Phenotyping Consortium}}</ref> to determine the effects of deletion.<ref name="pmid21677750">{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = Jun 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = Jun 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = Jan 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref><ref name="pmid23870131">{{cite journal | vauthors = White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP | title = Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes | journal = Cell | volume = 154 | issue = 2 | pages = 452–64 | date = Jul 2013 | pmid = 23870131 | pmc = 3717207 | doi = 10.1016/j.cell.2013.06.022 }}</ref> Additional screens performed:  - In-depth immunological phenotyping<ref name="iii_ref">{{cite web |url= http://www.immunophenotyping.org/data/search?keys=Pepd&field_gene_construct_tid=All |title=Infection and Immunity Immunophenotyping (3i) Consortium}}</ref>
{| class="wikitable sortable collapsible collapsed" border="1" cellpadding="2" style="float: left;" |
|+ ''Pepd'' knockout mouse phenotype
|-
! Characteristic!! Phenotype
|-
| colspan=2; style="text-align: center;" | All data available at.<ref name="IMPCsearch_ref"/><ref name="iii_ref" />
|-
| Homozygous viability at P14 || bgcolor="#488ED3"|Normal
 
|-
| Homozygous Fertility || bgcolor="#488ED3"|Normal
 
|-
| Body weight || bgcolor="#488ED3"|Normal
 
|-
| Neurological assessment || bgcolor="#488ED3"|Normal
 
|-
| Grip strength || bgcolor="#488ED3"|Normal
 
|-
| [[Dysmorphology]] || bgcolor="#488ED3"|Normal
 
|-
| [[Indirect calorimetry]] || bgcolor="#488ED3"|Normal
 
|-
| [[Glucose tolerance test]] || bgcolor="#488ED3"|Normal
 
|-
| [[Dual-energy X-ray absorptiometry|DEXA]] || bgcolor="#C40000"|Abnormal
 
|-
| Eye morphology || bgcolor="#488ED3"|Normal
 
|-
| [[Clinical chemistry]] || bgcolor="#488ED3"|Normal
 
|-
| ''[[Haematology]]'' 16 Weeks || bgcolor="#488ED3"|Normal
 
|-
| Peripheral blood leukocytes 16 Weeks || bgcolor="#488ED3"|Normal
 
|-
| Heart weight || bgcolor="#488ED3"|Normal
 
|-
| Cytotoxic T Cell Function || bgcolor="#488ED3"|Normal
 
|-
| Spleen Immunophenotyping || bgcolor="#488ED3"|Normal
 
|-
| Mesenteric Lymph Node Immunophenotyping || bgcolor="#488ED3"|Normal
 
|-
| Bone Marrow Immunophenotyping || bgcolor="#488ED3"|Normal
 
|-
| Epidermal Immune Composition || bgcolor="#488ED3"|Normal
 
|-
| Influenza Challenge || bgcolor="#488ED3"|Normal
 
|-
|}
{{clear|left}}
 
== References ==
{{reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Tanoue A, Endo F, Kitano A, Matsuda I | title = A single nucleotide change in the prolidase gene in fibroblasts from two patients with polypeptide positive prolidase deficiency. Expression of the mutant enzyme in NIH 3T3 cells | journal = The Journal of Clinical Investigation | volume = 86 | issue = 1 | pages = 351–5 | date = Jul 1990 | pmid = 2365824 | pmc = 296729 | doi = 10.1172/JCI114708 }}
* {{cite journal | vauthors = Boright AP, Scriver CR, Lancaster GA, Choy F | title = Prolidase deficiency: biochemical classification of alleles | journal = American Journal of Human Genetics | volume = 44 | issue = 5 | pages = 731–40 | date = May 1989 | pmid = 2705457 | pmc = 1715628 | doi =  }}
* {{cite journal | vauthors = Friedrich U, Brunner H, Smeets D, Lambermon E, Ropers HH | title = Three-point linkage analysis employing C3 and 19cen markers assigns the myotonic dystrophy gene to 19q | journal = Human Genetics | volume = 75 | issue = 3 | pages = 291–3 | date = Mar 1987 | pmid = 2881880 | doi = 10.1007/BF00281077 }}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1-2 | pages = 171–4 | date = Jan 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Ledoux P, Scriver C, Hechtman P | title = Four novel PEPD alleles causing prolidase deficiency | journal = American Journal of Human Genetics | volume = 54 | issue = 6 | pages = 1014–21 | date = Jun 1994 | pmid = 8198124 | pmc = 1918181 | doi =  }}
* {{cite journal | vauthors = Ledoux P, Scriver CR, Hechtman P | title = Expression and molecular analysis of mutations in prolidase deficiency | journal = American Journal of Human Genetics | volume = 59 | issue = 5 | pages = 1035–9 | date = Nov 1996 | pmid = 8900231 | pmc = 1914827 | doi =  }}
* {{cite journal | vauthors = Pałka JA | title = The role of prolidase as an enzyme participating in the metabolism of collagen | journal = Roczniki Akademii Medycznej W Białymstoku | volume = 41 | issue = 2 | pages = 149–60 | year = 1997 | pmid = 9020526 | doi =  }}
* {{cite journal | vauthors = Palka JA, Phang JM | title = Prolidase activity in fibroblasts is regulated by interaction of extracellular matrix with cell surface integrin receptors | journal = Journal of Cellular Biochemistry | volume = 67 | issue = 2 | pages = 166–75 | date = Nov 1997 | pmid = 9328822 | doi = 10.1002/(SICI)1097-4644(19971101)67:2<166::AID-JCB2>3.0.CO;2-V }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1-2 | pages = 149–56 | date = Oct 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
* {{cite journal | vauthors = Muszyńska A, Pałka J, Gorodkiewicz E | title = The mechanism of daunorubicin-induced inhibition of prolidase activity in human skin fibroblasts and its implication to impaired collagen biosynthesis | journal = Experimental and Toxicologic Pathology | volume = 52 | issue = 2 | pages = 149–55 | date = May 2000 | pmid = 10965990 | doi = 10.1016/s0940-2993(00)80108-6 }}
* {{cite journal | vauthors = Surazyński A, Pałka J | title = FAK-independent regulation of prolidase activity and collagen biosynthesis in MCF-7 cells | journal = Folia Histochemica et Cytobiologica | volume = 39 Suppl 2 | issue =  | pages = 212–3 | year = 2002 | pmid = 11820613 | doi =  }}
* {{cite journal | vauthors = Harris RA, Yang A, Stein RC, Lucy K, Brusten L, Herath A, Parekh R, Waterfield MD, O'Hare MJ, Neville MA, Page MJ, Zvelebil MJ | title = Cluster analysis of an extensive human breast cancer cell line protein expression map database | journal = Proteomics | volume = 2 | issue = 2 | pages = 212–23 | date = Feb 2002 | pmid = 11840567 | doi = 10.1002/1615-9861(200202)2:2<212::AID-PROT212>3.0.CO;2-H }}
* {{cite journal | vauthors = Forlino A, Lupi A, Vaghi P, Icaro Cornaglia A, Calligaro A, Campari E, Cetta G | title = Mutation analysis of five new patients affected by prolidase deficiency: the lack of enzyme activity causes necrosis-like cell death in cultured fibroblasts | journal = Human Genetics | volume = 111 | issue = 4-5 | pages = 314–22 | date = Oct 2002 | pmid = 12384772 | doi = 10.1007/s00439-002-0792-5 }}
* {{cite journal | vauthors = Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP | title = Large-scale characterization of HeLa cell nuclear phosphoproteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 33 | pages = 12130–5 | date = Aug 2004 | pmid = 15302935 | pmc = 514446 | doi = 10.1073/pnas.0404720101 }}
* {{cite journal | vauthors = Lupi A, De Riso A, Torre SD, Rossi A, Campari E, Vilarinho L, Cetta G, Forlino A | title = Characterization of a new PEPD allele causing prolidase deficiency in two unrelated patients: natural-occurrent mutations as a tool to investigate structure-function relationship | journal = Journal of Human Genetics | volume = 49 | issue = 9 | pages = 500–6 | year = 2004 | pmid = 15309682 | doi = 10.1007/s10038-004-0180-1 }}
{{refend}}
{{refend}}


{{protein-stub}}
{{PDB Gallery|geneid=5184}}
{{WikiDoc Sources}}

Revision as of 02:48, 28 October 2017

This article is about human gene PEPD. For the pain disorder, see Paroxysmal extreme pain disorder.
VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

n/a

n/a

Ensembl

n/a

n/a

UniProt

n/a

n/a

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Xaa-Pro dipeptidase, also known as prolidase, is an enzyme that in humans is encoded by the PEPD gene.[1][2][3]

Function

Xaa-Pro dipeptidase is a cytosolic dipeptidase that hydrolyzes dipeptides with proline or hydroxyproline at the carboxy terminus (but not Pro-Pro). It is important in collagen metabolism because of the high levels of imino acids.[3] Mutations at the PEPD locus cause prolidase deficiency. This is characterised by Iminodipeptidurea, skin ulcers, mental retardation and recurrent infections.

Structure

Prolidases fall under a subclass of metallopeptidases that involve binuclear active site metal clusters.[4] This metal cluster facilitates catalysis by serving as a substrate binding site, activating nucleophiles, and stabilizing the transition state. Furthermore, prolidases are classified under a smaller family called “pita-bread” enzymes, which cleave amido-, imido-, and amidino- containing bonds.[5] The “pita-bread” fold, containing a metal center flanked by two well-defined substrate binding pockets enabled prolidase to specifically cleave between any non-proline amino acid and proline.

Prolidase cleavage of peptide to yield alanine and proline

The first ever solved structure of prolidase came from the hyperthermophilic archaeon Pyrococcus furiosus (Pfprol).[4] This dimer has a crystal structure shows two approximately symmetrical monomers that both have an N-terminal domain, made up of a six-stranded mixed β-sheet flanked by five α-helices, a helical linker, and C-terminal domain, consisting of a mixed six-stranded β-sheet flanked by four α-helices. The curved β-sheet of Domain II has a “pita-bread” fold. The active site lies on the inner surface of the β-sheet of Domain II, with a notable dinuclear Co cluster anchored by the side chains of two aspartate residues (Asp209 and Asp220), two glutamate residues (Glu313 and Glu327), and a histidine residue (His284). Carboxylate groups of aspartate and glutamine residues serve as bridges between the two Co atoms. In the crystallization process, the Co atoms are replaced with Zn, which hinders enzymatic activity.

Unlike Pfprol, the structure of the human variant remains poorly understood. Sequence homology between human and Pfprol yield only 25% identity and 43% similarity.[6] The two available structures of human prolidase available on the Protein Data Bank are homodimers contain either Na or Mn, which bind to similar amino acids as those in Pfprol: Glu412 (Glu313 in Pfprol), binds to the first ion, Asp276 (Asp209 in Pfprol) binds to the second ion, and Asp287 and Glu452 bind to both (Asp220 and Glu327 in Pfprol).

File:Pfprol active site.png
Asp209, Asp220, Glu313, Glu327, and His284 make up the active site of prolidase from Pyrococcus furiosus (1PV9). The zinc ions are bridged by the carboxylate groups of aspartate and glutamine residues. Bond lengths between the zinc ions and carboxylate groups of the amino acids are also indicated.

Function

Due to proline’s cyclic structure, only few peptidases could cleave the bond between proline and other amino acids.[7] Along with prolinase, prolidase are the only known enzymes that can break down dipeptides to yield free proline. Prolidase serve to hydrolyze both dietary and endogenous Xaa-Pro dipeptides. More specifically, it is essential in catalyzing the last step of the degradation of procollagen, collagen, and other proline-containing peptides into free amino acids to be used for cellular growth.[8] Additionally, it also participates in the process of recycling proline from Xaa-Pro dipeptides for collagen resynthesis. Proline and hydroyxyproline make up a quarter of the amino acid residues in collegen, which is the most abundant protein in the body by mass and plays an important role in maintaining connective tissue in the body.[8][9]

Mechanism

The mechanism for prolidase catalytic activity remains largely uncharacterized.[10] However, biochemical and structural analyses of aminopeptidase (APPro), methionine aminopeptidase (MetAP), and prolidase, all members of the “pita-bread” metalloenzymes, suggest that they share a common mechanism scheme.[5] The main difference arises in the location of the carbonyl oxygen atom of the scissile peptide bond.

File:Proposed mechanism scheme for metal-dependent "pita-bread" enzyme with eMetAP residue numbering.png
Proposed mechanism scheme for metal-dependent "pita-bread" enzyme with eMetAP residue numbering.[5]

The following mechanism shows a proposed scheme for a metal-dependent “pita-bread” enzyme with residue numbering corresponding to those found in methionine aminopeptidase from E. coli.[5] As shown in Intermediate I of the figure, three potential acidic amino acid residues interact with the N-terminus of the substrate in a fashion that is yet to be determined. The carbonyl and amide groups of the scissile peptide bond interact with the first metal ion, M1, in addition to His178 and His79, respectively. M1 and Glu204 activate a water molecule to prepare it nucleophilic attack at the carbonyl carbon of the scissile peptide bond. Then, the tetrahedral intermediate (Intermediate II) becomes stabilized from interactions with M1 and His178. Lastly, Glu204 donates a proton to the amine of the leaving peptide (P1’). This leads to the breakdown of the intermediate (Intermediate III), which retains its interactions with M1 and His178.

Regulation

Post-translational modifications of prolidase regulate its enzymatic abilities. Phosphorylation of prolidase has been shown to increase its activity while dephosphorylation leads to a decrease in enzyme activity.[11] Analysis of known consensus sequence required for serine/threonine phosphorylation revealed that prolidase contains at least three potential sites for serine/threonine phosphorylation. Nitric oxide, both exogenously acquired and endogenously generated, was shown to increase prolidase activity in a time- and dose-dependent manner via phosphorylation at these serine and threonine sites.[12] Additionally, prolidase may also be regulated at tyrosine phosphorylation sites, which are mediated by FAK and MAPK signaling pathways.[11]

Disease relevance

Deficiency in prolidase leads to a rare, severe autosomal recessive disorder (prolidase deficiency) that causes many chronic, debilitating health conditions in humans.[13] These phenotypical symptoms vary and may include skin ulcerations, mental retardation, splenomegaly, recurrent infections, photosensitivity, hyperkeratosis, and unusual facial appearance. Furthermore, prolidase activity was found to be abnormal compared to healthy levels in various medical conditions including but limited to: bipolar disorder, breast cancer, endometrial cancer, keloid scar formation, erectile dysfunction, liver disease, lung cancer, hypertension, melanoma, and chronic pancreatitis.[7] In some cancers with increased levels of prolidase activity, such as melanoma, the differential expression of prolidase and its substrate specificity for dipeptides with proline at the carboxyl end suggests the potential of prolidase in becoming a viable, selective endogenous enzyme target for proline prodrugs.[14] Serum prolidase enzyme activity is also currently being explored as a possible, reliable marker for diseases including chronic hepatitis B and liver fibrosis.[15][16][17]

Other applications

Decontamination: Prolidase from the hyperthermophilic archaeon Pyrococcus furiosus (Pfprol) shows potential for application in decontamination of organophosphorus nerve agents in chemical warfare agents.[18] Additionally, prolidase could also serve to detect fluorine-containing organophosphorus neurotoxins, like the G-type chemical warfare agents, and could antagonize organophosphorous intoxication and protect against the effects of diisopropylfluorophosphate when encapsulated in liposomes.[19][20]

Model organisms

Model organisms have been used in the study of PEPD function. A conditional knockout mouse line called Pepdtm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[21] Male and female animals underwent a standardized phenotypic screen[22] to determine the effects of deletion.[23][24][25][26] Additional screens performed: - In-depth immunological phenotyping[27]

References

  1. ↑ Endo F, Tanoue A, Nakai H, Hata A, Indo Y, Titani K, Matsuda I (Mar 1989). "Primary structure and gene localization of human prolidase". The Journal of Biological Chemistry. 264 (8): 4476–81. PMID 2925654.
  2. ↑ Tanoue A, Endo F, Matsuda I (Jul 1990). "Structural organization of the gene for human prolidase (peptidase D) and demonstration of a partial gene deletion in a patient with prolidase deficiency". The Journal of Biological Chemistry. 265 (19): 11306–11. PMID 1972707.
  3. ↑ 3.0 3.1 "Entrez Gene: PEPD peptidase D".
  4. ↑ 4.0 4.1 Maher MJ, Ghosh M, Grunden AM, Menon AL, Adams MW, Freeman HC, Guss JM (Mar 2004). "Structure of the prolidase from Pyrococcus furiosus". Biochemistry. 43 (10): 2771–83. doi:10.1021/bi0356451. PMID 15005612.
  5. ↑ 5.0 5.1 5.2 5.3 Lowther WT, Matthews BW (Dec 2002). "Metalloaminopeptidases: common functional themes in disparate structural surroundings". Chemical Reviews. 102 (12): 4581–608. doi:10.1021/cr0101757. PMID 12475202.
  6. ↑ Lupi A, Tenni R, Rossi A, Cetta G, Forlino A (Nov 2008). "Human prolidase and prolidase deficiency: an overview on the characterization of the enzyme involved in proline recycling and on the effects of its mutations". Amino Acids. 35 (4): 739–52. doi:10.1007/s00726-008-0055-4. PMID 18340504.
  7. ↑ 7.0 7.1 Kitchener RL, Grunden AM (Aug 2012). "Prolidase function in proline metabolism and its medical and biotechnological applications". Journal of Applied Microbiology. 113 (2): 233–47. doi:10.1111/j.1365-2672.2012.05310.x. PMID 22512465.
  8. ↑ 8.0 8.1 Surazynski A, Miltyk W, Palka J, Phang JM (Nov 2008). "Prolidase-dependent regulation of collagen biosynthesis". Amino Acids. 35 (4): 731–8. doi:10.1007/s00726-008-0051-8. PMID 18320291.
  9. ↑ Phang JM, Donald SP, Pandhare J, Liu Y (Nov 2008). "The metabolism of proline, a stress substrate, modulates carcinogenic pathways". Amino Acids. 35 (4): 681–90. doi:10.1007/s00726-008-0063-4. PMID 18401543.
  10. ↑ Graham SC, Lilley PE, Lee M, Schaeffer PM, Kralicek AV, Dixon NE, Guss JM (Jan 2006). "Kinetic and crystallographic analysis of mutant Escherichia coli aminopeptidase P: insights into substrate recognition and the mechanism of catalysis". Biochemistry. 45 (3): 964–75. doi:10.1021/bi0518904. PMID 16411772.
  11. ↑ 11.0 11.1 Surazyński A, Pałka J, Wołczyński S (Apr 2001). "Phosphorylation of prolidase increases the enzyme activity". Molecular and Cellular Biochemistry. 220 (1–2): 95–101. doi:10.1023/a:1010849100540. PMID 11451388.
  12. ↑ Surazynski A, Liu Y, Miltyk W, Phang JM (Dec 2005). "Nitric oxide regulates prolidase activity by serine/threonine phosphorylation". Journal of Cellular Biochemistry. 96 (5): 1086–94. doi:10.1002/jcb.20631. PMID 16167338.
  13. ↑ Viglio S, Annovazzi L, Conti B, Genta I, Perugini P, Zanone C, Casado B, Cetta G, Iadarola P (Feb 2006). "The role of emerging techniques in the investigation of prolidase deficiency: from diagnosis to the development of a possible therapeutical approach". Journal of Chromatography B. 832 (1): 1–8. doi:10.1016/j.jchromb.2005.12.049. PMID 16434239.
  14. ↑ Mittal S, Song X, Vig BS, Landowski CP, Kim I, Hilfinger JM, Amidon GL (2005). "Prolidase, a potential enzyme target for melanoma: design of proline-containing dipeptide-like prodrugs". Molecular Pharmaceutics. 2 (1): 37–46. doi:10.1021/mp049922p. PMID 15804176.
  15. ↑ Şen V, Uluca Ü, Ece A, Kaplan İ, Bozkurt F, Aktar F, Bağlı S, Tekin R (Nov 2014). "Serum prolidase activity and oxidant-antioxidant status in children with chronic hepatitis B virus infection". Italian Journal of Pediatrics. 40 (1): 95. doi:10.1186/s13052-014-0095-1. PMC 4247636. PMID 25425101.
  16. ↑ Duygu F, Aksoy N, Cicek AC, Butun I, Unlu S (Sep 2013). "Does prolidase indicate worsening of hepatitis B infection?". Journal of Clinical Laboratory Analysis. 27 (5): 398–401. doi:10.1002/jcla.21617. PMID 24038226.
  17. ↑ Stanfliet JC, Locketz M, Berman P, Pillay TS (May 2015). "Evaluation of the utility of serum prolidase as a marker for liver fibrosis". Journal of Clinical Laboratory Analysis. 29 (3): 208–13. doi:10.1002/jcla.21752. PMID 24798655.
  18. ↑ Theriot CM, Du X, Tove SR, Grunden AM (Aug 2010). "Improving the catalytic activity of hyperthermophilic Pyrococcus prolidases for detoxification of organophosphorus nerve agents over a broad range of temperatures". Applied Microbiology and Biotechnology. 87 (5): 1715–26. doi:10.1007/s00253-010-2614-3. PMID 20422176.
  19. ↑ Simonian AL, Grimsley JK, Flounders AW, Schoeniger JS, Cheng TC, Defrank JJ, Wild JR (2001). "Enzyme-based biosensor for the direct detection of fluorine-containing organophosphates". Analytica Chimica Acta. 442: 15–23. doi:10.1016/S0003-2670(01)01131-X.
  20. ↑ Petrikovics I, Cheng TC, Papahadjopoulos D, Hong K, Yin R, DeFrank JJ, Jaing J, Song ZH, McGuinn WD, Sylvester D, Pei L, Madec J, Tamulinas C, Jaszberenyi JC, Barcza T, Way JL (Sep 2000). "Long circulating liposomes encapsulating organophosphorus acid anhydrolase in diisopropylfluorophosphate antagonism". Toxicological Sciences. 57 (1): 16–21. doi:10.1093/toxsci/57.1.16. PMID 10966507.
  21. ↑ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
  22. ↑ 22.0 22.1 "International Mouse Phenotyping Consortium".
  23. ↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  24. ↑ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  25. ↑ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  26. ↑ White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (Jul 2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell. 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131.
  27. ↑ 27.0 27.1 "Infection and Immunity Immunophenotyping (3i) Consortium".

Further reading

Retrieved from "https://www.wikidoc.org/index.php?title=PEPD&oldid=1418747"