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Complementary data on Proline racemase published in different journals (references indicated) and some corrections or precisions about the enzyme.
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:L-proline <math>\rightleftharpoons</math> D-proline
:L-proline <math>\rightleftharpoons</math> D-proline


Hence, this enzyme has one [[substrate (biochemistry)|substrate]], [[L-proline]], and one [[product (chemistry)|product]], [[D-proline]].
Hence, this enzyme has two [[substrates (biochemistry)|substrate]]s, [[L- and D- proline]], and two [[products (chemistry)|product]]s, [[D- and L- proline]].


This enzyme belongs to the family of [[isomerase]]s, specifically those [[racemase]]s and [[epimerase]]s acting on [[amino acid]]s and derivatives. The systematic name of this enzyme class is '''proline racemase'''. This enzyme participates in [[arginine]] and [[proline]] metabolism. These enzymes catalyse the interconversion of L- and D-proline in bacteria.<ref name="PUB00011432">{{cite journal |author=Knowles JR, Fisher LM, Albery WJ |title=Energetics of proline racemase: racemization of unlabeled proline in the unsaturated, saturated, and oversaturated regimes |journal=Biochemistry |volume=25 |issue=9 |pages=2529–2537 |year=1986 |pmid=3755058 |doi=10.1021/bi00357a037}}</ref> This family also contains several similar eukaryotic proteins including {{Uniprot|Q9NCP4}} a sequence with B-cell mitogenic properties which has been characterised as a co-factor-independent proline racemase.<ref name="PUB00011433">{{cite journal |author=Reina-san-martin B, Degrave W, Rougeot C, Cosson A, Chamond N, Cordeiro-da-silva A, Arala-chaves M, Coutinho A, Minoprio P |title=A B-cell mitogen from a pathogenic trypanosome is a eukaryotic proline racemase |journal=Nat. Med. |volume=6 |issue=8 |pages=890–897 |year=2000 |pmid=10932226 |doi=10.1038/78651}}</ref>
This enzyme belongs to the family of proline racemases acting on free [[amino acid]]s. The systematic name of this enzyme class is '''proline racemase'''. This enzyme participates in [[arginine]] and [[proline]] metabolism. These enzymes catalyse the interconversion of L- and D-proline in bacteria.<ref name="PUB00011432">{{cite journal |author=Knowles JR, Fisher LM, Albery WJ |title=Energetics of proline racemase: racemization of unlabeled proline in the unsaturated, saturated, and oversaturated regimes |journal=Biochemistry |volume=25 |issue=9 |pages=2529–2537 |year=1986 |pmid=3755058 |doi=10.1021/bi00357a037}}</ref>.

This first eukaryotic proline racemase was identified in ''Trypanosoma cruzi'' and fully characterized {{Uniprot|Q9NCP4}}. The parasite enzyme, ''Tc''PRAC, is as a co-factor-independent proline racemase and displays B-cell mitogenic properties when released by ''T. cruzi'' upon infection, contributing to parasite escape.<ref name="PUB00011433">{{cite journal |author=Reina-san-martin B, Degrave W, Rougeot C, Cosson A, Chamond N, Cordeiro-da-silva A, Arala-chaves M, Coutinho A, Minoprio P |title=A B-cell mitogen from a pathogenic trypanosome is a eukaryotic proline racemase |journal=Nat. Med. |volume=6 |issue=8 |pages=890–897 |year=2000 |pmid=10932226 |doi=10.1038/78651}}</ref> <ref>Chamond, N., C. Gregoire, N. Coatnoan, C. Rougeot, L. H. Freitas, J. F. da Silveira, W. M. Degrave, and P. Minoprio (2003) « "Biochemical characterization of proline racemases from the human protozoan parasite ''Trypanosoma cruzi'' and definition of putative protein signatures". J. Biol. Chem. 278 (18):15484-15494. [http://Doi%20:%2010.1074/Jbc.M210830200.%20PMID:%2016164548 Doi : 10.1074/Jbc.M210830200. PMID: 16164548].</ref>

Novel proline racemases of medical and veterinary importance were described respectively in ''Clostridium difficile'' (Q17ZY4)<ref>Goytia, M., N. Chamond, A. Cosson, N. Coatnoan, D. Hermant, A. Berneman, and P. Minoprio. (2007) "Molecular and structural discrimination of proline racemase and hydroxyproline-2-epimerase from nosocomial and bacterial pathogens". ''PLoS ONE'' '''2''':e885. [http://doi:10.1371/journal.pone.0000885.%20PMID:%2017849014 doi:10.1371/journal.pone.0000885. PMID: 17849014].</ref> and ''Trypanosoma vivax'' (B8LFE4). <ref>Chamond, N., A. Cosson, N. Coatnoan, and P. Minoprio (2009) "Proline racemases are conserved mitogens: characterization of a ''Trypanosoma vivax'' proline racemase". ''Mol Biochem Parasitol'' '''165''' (2) :170-179. [http://doi:10.1016/j.molbiopara.2009.02.002.%20PMID:%2019428664 doi:10.1016/j.molbiopara.2009.02.002. PMID: 19428664]</ref> These studies showed that a peptide motif used as a minimal pattern signature to identify putative proline racemases (motif III*) is insufficient stringent ''per se'' to discriminate proline racemases from 4-hydroxyproline epimerases (HyPRE). Also, additional, non-dissociated elements that account for the discrimination of these enzymes were identified, based for instance on polarity constraints imposed by specific residues of the catalytic pockets. Based on those elements, enzymes incorrectly described as proline racemases were biochemically proved to be hydroxyproline epimerases (i.e. HyPREs from ''Pseudomonas aeruginosa'' (Q9I476), ''Burkholderia pseudomallei'' (Q63NG7), ''Brucella abortus'' (Q57B94), ''Brucella suis'' (Q8FYS0) and ''Brucella mellitensis'' (Q8YJ29))


==Structural studies==
==Structural studies==


The biochemical mechanism of proline racemase was first put forward in the late sixties by Cardinale and Abeles<ref>Cardinale, G., J. Abeles, R. H. (1968) "Purification and mechanism of action of proline racemase". ''Biochemistry'' '''7''' (11): 3970-3978. doi: [http://10.1021/bi00851a026.%20PMID:%205722267 10.1021/bi00851a026. PMID: 5722267]</ref> using the ''Clostridium sticklandii'' enzyme, ''Cs''PRAC. The catalytic mechanism of proline [[racemase]] was late revisited by Buschiazzo, Goytia and collaborators that, in 2006, resolved the structure of the parasite ''Tc''PRAC co-crystallyzed with its known competitive inhibitor - pyrrole carboxylic acid (PYC), with [[Protein Data Bank|PDB]] accession codes {{PDB link|1W61}}, and {{PDB link|1W62}}.<ref>Buschiazzo, A. Goytia, M. Schaeffer, F. Degrave, W. Shepard, W. Gregoire, C. Chamond, N. Cosson, A. Berneman, A. Coatnoan, N. Alzari, P. M. Minoprio, P. (2006) "Crystal structure, catalytic mechanism, and mitogenic properties of ''Trypanosoma cruzi'' proline racemase" ''Proc Natl Acad Sci U S A.'' '''103''' (6) : 1705-1710. [http://doi:%2010.1073/pnas.0509010103%20.%20PMID:%2016446443 doi: 10.1073/pnas.0509010103 . PMID: 16446443]</ref>. Those studies showed that each active enzyme contains two catalytic pockets. Isothermal calorimetry then showed that two molecules of PYC associate with ''Tc''PRAC in solution, and that this association is time-dependent and most probably based on mechanism of negative cooperativity. Complementary biochemical findings are consistent with the presence of two active catalytic sites per homodimer, each pertaining to one enzyme subunit, challenging the previously proposed mechanism of one catalytic site per homodimer proposed by Cardinale and Abeles.
As of late 2007, 3 [[tertiary structure|structures]] have been solved for this class of enzymes, with [[Protein Data Bank|PDB]] accession codes {{PDB link|1TM0}}, {{PDB link|1W61}}, and {{PDB link|1W62}}.


==References==
==References==
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== Further reading ==
== Further reading ==
{{refbegin}}
{{refbegin}}
* {{cite journal | author = Stadtman TC and Elliott P | title = Studies on the enzymic reduction of amino acids. II. Purification and properties of D-proline reductase and a proline racemase from Clostridium sticklandii | journal = J. Biol. Chem. | volume = 228 | issue = 2 | pages = 983–97 | year = 1957 | month = October | pmid = 13475375 | doi = | url = | issn = }}
* {{cite journal | author = Stadtman TC and Elliott P | title = Studies on the enzymic reduction of amino acids. II. Purification and properties of D-proline reductase and a proline racemase from ''Clostridium sticklandii'' | journal = J. Biol. Chem. | volume = 228 | issue = 2 | pages = 983–97 | year = 1957 | month = October | pmid = 13475375 | doi = | url = | issn = }}
* {{cite journal | author = Stenta M, Calvaresi M, Altoè P, Spinelli D, Garavelli M, Bottoni A | title = The catalytic activity of proline racemase: a quantum mechanical/molecular mechanical study | journal = J Phys Chem B | volume = 112 | issue = 4 | pages = 1057–9 | year = 2008 | month = January | pmid = 18044876 | doi = 10.1021/jp7104105 | url = | issn = }}
* {{cite journal | author = Stenta M, Calvaresi M, Altoè P, Spinelli D, Garavelli M, Bottoni A | title = The catalytic activity of proline racemase: a quantum mechanical/molecular mechanical study | journal = J Phys Chem B | volume = 112 | issue = 4 | pages = 1057–9 | year = 2008 | month = January | pmid = 18044876 | doi = 10.1021/jp7104105 | url = | issn = }}
{{refend}}
{{refend}}
* Chamond, N., M. Goytia, N. Coatnoan, J. C. Barale, A. Cosson, W. M. Degrave, and P. Minoprio (2005). « ''Trypanosoma cruzi'' proline racemases are involved in parasite differentiation and infectivity ». Mol Microbiol 58 (1):46-60. [http://doi%20:%2010.1111/j.1365-2958.2005.04808.x.%20PMID:%2016164548 doi : 10.1111/j.1365-2958.2005.04808.x. PMID: 16164548]
* Chamond, N., A. Cosson, M. C. Blom-Potar, G. Jouvion, S. D'Archivio, M. Medina, S. Droin-Bergere, M. Huerre, S. Goyard, and P. Minoprio (2010) « ''Trypanosoma vivax'' infections: pushing ahead with mouse models for the study of Nagana. I. Parasitological, hematological and pathological parameters ». PLoS Negl Trop Dis 4:e792. [http://doi%20:%2010.1371/journal.pntd.0000792.%20PMID:%2020706595 doi : 10.1371/journal.pntd.0000792. PMID: 20706595]
* Blom-Potar, M. C., N. Chamond, A. Cosson, G. Jouvion, S. Droin-Bergere, M. Huerre, and P. Minoprio (2010) « ''Trypanosoma vivax'' infections: pushing ahead with mouse models for the study of Nagana. II. Immunobiological dysfunctions ». PLoS Negl Trop Dis 4:e793. [http://doi%20:%2010.1371/journal.pntd.0000793.%20PMID:%2020711524 doi : 10.1371/journal.pntd.0000793. PMID: 20711524]
* Conti, P., L. Tamborini, A. Pinto, A. Blondel, P. Minoprio, A. Mozzarelli, and De Micheli. (2011) Sep 13. [Epub ahead of print] « Drug Discovery Targeting Amino Acid Racemases ». Chem. Rev. [http://dx.doi/10.1021/cr20000702.%20PMID:%2021913633 dx.doi/10.1021/cr20000702. PMID: 21913633]



{{isomerase-stub}}
{{isomerase-stub}}

Revision as of 16:28, 7 October 2011

proline racemase
Identifiers
EC no.5.1.1.4
CAS no.9024-09-3
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
Proline racemase
Identifiers
SymbolPro_racemase
PfamPF05544
InterProIPR008794
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB2azpA:6-313 1tm0B:9-333

In enzymology, a proline racemase (EC 5.1.1.4) is an enzyme that catalyzes the chemical reaction

L-proline D-proline

Hence, this enzyme has two substrates, L- and D- proline, and two products, D- and L- proline.

This enzyme belongs to the family of proline racemases acting on free amino acids. The systematic name of this enzyme class is proline racemase. This enzyme participates in arginine and proline metabolism. These enzymes catalyse the interconversion of L- and D-proline in bacteria.[1].

This first eukaryotic proline racemase was identified in Trypanosoma cruzi and fully characterized Q9NCP4. The parasite enzyme, TcPRAC, is as a co-factor-independent proline racemase and displays B-cell mitogenic properties when released by T. cruzi upon infection, contributing to parasite escape.[2] [3]

Novel proline racemases of medical and veterinary importance were described respectively in Clostridium difficile (Q17ZY4)[4] and Trypanosoma vivax (B8LFE4). [5] These studies showed that a peptide motif used as a minimal pattern signature to identify putative proline racemases (motif III*) is insufficient stringent per se to discriminate proline racemases from 4-hydroxyproline epimerases (HyPRE). Also, additional, non-dissociated elements that account for the discrimination of these enzymes were identified, based for instance on polarity constraints imposed by specific residues of the catalytic pockets. Based on those elements, enzymes incorrectly described as proline racemases were biochemically proved to be hydroxyproline epimerases (i.e. HyPREs from Pseudomonas aeruginosa (Q9I476), Burkholderia pseudomallei (Q63NG7), Brucella abortus (Q57B94), Brucella suis (Q8FYS0) and Brucella mellitensis (Q8YJ29))

Structural studies

The biochemical mechanism of proline racemase was first put forward in the late sixties by Cardinale and Abeles[6] using the Clostridium sticklandii enzyme, CsPRAC. The catalytic mechanism of proline racemase was late revisited by Buschiazzo, Goytia and collaborators that, in 2006, resolved the structure of the parasite TcPRAC co-crystallyzed with its known competitive inhibitor - pyrrole carboxylic acid (PYC), with PDB accession codes 1W61, and 1W62.[7]. Those studies showed that each active enzyme contains two catalytic pockets. Isothermal calorimetry then showed that two molecules of PYC associate with TcPRAC in solution, and that this association is time-dependent and most probably based on mechanism of negative cooperativity. Complementary biochemical findings are consistent with the presence of two active catalytic sites per homodimer, each pertaining to one enzyme subunit, challenging the previously proposed mechanism of one catalytic site per homodimer proposed by Cardinale and Abeles.

References

  1. ^ Knowles JR, Fisher LM, Albery WJ (1986). "Energetics of proline racemase: racemization of unlabeled proline in the unsaturated, saturated, and oversaturated regimes". Biochemistry. 25 (9): 2529–2537. doi:10.1021/bi00357a037. PMID 3755058.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Reina-san-martin B, Degrave W, Rougeot C, Cosson A, Chamond N, Cordeiro-da-silva A, Arala-chaves M, Coutinho A, Minoprio P (2000). "A B-cell mitogen from a pathogenic trypanosome is a eukaryotic proline racemase". Nat. Med. 6 (8): 890–897. doi:10.1038/78651. PMID 10932226.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Chamond, N., C. Gregoire, N. Coatnoan, C. Rougeot, L. H. Freitas, J. F. da Silveira, W. M. Degrave, and P. Minoprio (2003) « "Biochemical characterization of proline racemases from the human protozoan parasite Trypanosoma cruzi and definition of putative protein signatures". J. Biol. Chem. 278 (18):15484-15494. Doi : 10.1074/Jbc.M210830200. PMID: 16164548.
  4. ^ Goytia, M., N. Chamond, A. Cosson, N. Coatnoan, D. Hermant, A. Berneman, and P. Minoprio. (2007) "Molecular and structural discrimination of proline racemase and hydroxyproline-2-epimerase from nosocomial and bacterial pathogens". PLoS ONE 2:e885. doi:10.1371/journal.pone.0000885. PMID: 17849014.
  5. ^ Chamond, N., A. Cosson, N. Coatnoan, and P. Minoprio (2009) "Proline racemases are conserved mitogens: characterization of a Trypanosoma vivax proline racemase". Mol Biochem Parasitol 165 (2) :170-179. doi:10.1016/j.molbiopara.2009.02.002. PMID: 19428664
  6. ^ Cardinale, G., J. Abeles, R. H. (1968) "Purification and mechanism of action of proline racemase". Biochemistry 7 (11): 3970-3978. doi: 10.1021/bi00851a026. PMID: 5722267
  7. ^ Buschiazzo, A. Goytia, M. Schaeffer, F. Degrave, W. Shepard, W. Gregoire, C. Chamond, N. Cosson, A. Berneman, A. Coatnoan, N. Alzari, P. M. Minoprio, P. (2006) "Crystal structure, catalytic mechanism, and mitogenic properties of Trypanosoma cruzi proline racemase" Proc Natl Acad Sci U S A. 103 (6) : 1705-1710. doi: 10.1073/pnas.0509010103 . PMID: 16446443

Further reading

  • Stadtman TC and Elliott P (1957). "Studies on the enzymic reduction of amino acids. II. Purification and properties of D-proline reductase and a proline racemase from Clostridium sticklandii". J. Biol. Chem. 228 (2): 983–97. PMID 13475375. {{cite journal}}: Unknown parameter |month= ignored (help)
  • Stenta M, Calvaresi M, Altoè P, Spinelli D, Garavelli M, Bottoni A (2008). "The catalytic activity of proline racemase: a quantum mechanical/molecular mechanical study". J Phys Chem B. 112 (4): 1057–9. doi:10.1021/jp7104105. PMID 18044876. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  • Chamond, N., M. Goytia, N. Coatnoan, J. C. Barale, A. Cosson, W. M. Degrave, and P. Minoprio (2005). « Trypanosoma cruzi proline racemases are involved in parasite differentiation and infectivity ». Mol Microbiol 58 (1):46-60. doi : 10.1111/j.1365-2958.2005.04808.x. PMID: 16164548
  • Chamond, N., A. Cosson, M. C. Blom-Potar, G. Jouvion, S. D'Archivio, M. Medina, S. Droin-Bergere, M. Huerre, S. Goyard, and P. Minoprio (2010) « Trypanosoma vivax infections: pushing ahead with mouse models for the study of Nagana. I. Parasitological, hematological and pathological parameters ». PLoS Negl Trop Dis 4:e792. doi : 10.1371/journal.pntd.0000792. PMID: 20706595
  • Blom-Potar, M. C., N. Chamond, A. Cosson, G. Jouvion, S. Droin-Bergere, M. Huerre, and P. Minoprio (2010) « Trypanosoma vivax infections: pushing ahead with mouse models for the study of Nagana. II. Immunobiological dysfunctions ». PLoS Negl Trop Dis 4:e793. doi : 10.1371/journal.pntd.0000793. PMID: 20711524
  • Conti, P., L. Tamborini, A. Pinto, A. Blondel, P. Minoprio, A. Mozzarelli, and De Micheli. (2011) Sep 13. [Epub ahead of print] « Drug Discovery Targeting Amino Acid Racemases ». Chem. Rev. dx.doi/10.1021/cr20000702. PMID: 21913633


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