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== Introduction ==
== Introduction ==
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'''MraY''', called also '''phospho-N-acetylmuramoyl-pentapeptide-transferase''' or '''UDP-MurNAc-pentapeptide phosphotransferase''', with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.8.13 2.7.8.13], is an integral membrane enzyme involved in peptidoglycan biosynthesis <ref name="one">PMID:29778697</ref> <ref name="two">PMID:27511599</ref>.MraY is encoded by the mraY gene and belongs to a subfamily of the polyprenyl-phosphate N-acetyl hexosamine 1-phosphate transferase (PNPT) superfamily <ref name="three">PMID:23990562</ref>. MRAY is a promising candidate for the development of new antibiotics. In fact, it is the target of five classes of natural nucleoside inhibitors with potent antibacterial activity: the liposidomycins/caprazamycins, capuramycins, mureidomycins, muraymycins, and tunicamycins <ref name="two"/> <ref name="four">PMID:29438582</ref>.The structure presented in this page correspond to the MraY protein from ''Aquifex aeolicus'' (strain VF5), expressed in ''Escherichia coli'', in complex with carbacaprazamycin .<scene name='42/421575/Carbacaprazamycin/1'>Carbacaprazamycin</scene> is a chemically stable analog of caprazamycin nucleoside inhibitors <ref name="more1">DOI:10.1021/id5000376</ref>.
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'''<scene name='42/421575/Mray/1'>MraY</scene>''', called also '''phospho-N-acetylmuramoyl-pentapeptide-transferase''' or '''UDP-MurNAc-pentapeptide phosphotransferase''', with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.8.13 2.7.8.13], is an integral membrane enzyme involved in peptidoglycan biosynthesis <ref name="one">PMID:29778697</ref> <ref name="two">PMID:27511599</ref>.MraY is encoded by the mraY gene and belongs to a subfamily of the polyprenyl-phosphate N-acetyl hexosamine 1-phosphate transferase (PNPT) superfamily <ref name="three">PMID:23990562</ref>. MRAY is a promising candidate for the development of new antibiotics. In fact, it is the target of five classes of natural nucleoside inhibitors with potent antibacterial activity: the liposidomycins/caprazamycins, capuramycins, mureidomycins, muraymycins, and tunicamycins <ref name="two"/> <ref name="four">PMID:29438582</ref>.The structure presented in this page correspond to the MraY protein from ''Aquifex aeolicus'' (strain VF5), expressed in ''Escherichia coli'', in complex with carbacaprazamycin .<scene name='42/421575/Carbacaprazamycin/1'>Carbacaprazamycin</scene> is a chemically stable analog of caprazamycin nucleoside inhibitors <ref name="more1">DOI:10.1021/id5000376</ref>.
Drug resistant bacteria are the cause of death of millions of people worldwide. In the USA alone, hospital infections associated with antibiotic-resistant pathogens cause 99 000 deaths per year<ref name="more2">PMID:30349322</ref>. The development of new antibiotics with new mechanism of action is urgent. Structural analysis of the binding of carbacaprazamycin to MraY provides a better understanding of the chemical logic of MraY inhibition, which can help in the development of novel approaches for the design of antibiotics targeting MraY.
Drug resistant bacteria are the cause of death of millions of people worldwide. In the USA alone, hospital infections associated with antibiotic-resistant pathogens cause 99 000 deaths per year<ref name="more2">PMID:30349322</ref>. The development of new antibiotics with new mechanism of action is urgent. Structural analysis of the binding of carbacaprazamycin to MraY provides a better understanding of the chemical logic of MraY inhibition, which can help in the development of novel approaches for the design of antibiotics targeting MraY.
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== Function ==
== Function ==
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MraY is a critical enzyme in '''peptidoglycan biosynthesis'''. Peptidoglycan is an essential component of the cell wall of Gramnegative and Gram-positive bacteria <ref name="five">DOI:10.1039/b816215h</ref>. The cell wall provides bacteria a structural support and protection. In particular, it allows bacteria to maintain their cell shape at different osmotic pressures <ref name="six">PMID:26370936</ref>. Peptidoglycan is a cross-linked polymer of carbohydrates an amino acids and due to its biological relevance in Bacteria, it has been a major target for antibiotics <ref name="three"/> <ref name="five"/>.
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<scene name='42/421575/Mray/1'>MraY</scene> is a critical enzyme in '''peptidoglycan biosynthesis'''. Peptidoglycan is an essential component of the cell wall of Gramnegative and Gram-positive bacteria <ref name="five">DOI:10.1039/b816215h</ref>. The cell wall provides bacteria a structural support and protection. In particular, it allows bacteria to maintain their cell shape at different osmotic pressures <ref name="six">PMID:26370936</ref>. Peptidoglycan is a cross-linked polymer of carbohydrates an amino acids and due to its biological relevance in Bacteria, it has been a major target for antibiotics <ref name="three"/> <ref name="five"/>.
Peptidoglycan biosynthesis involves three main stages. MraY is responsible for the second stage. First, the peptidoglycan precursor UDP-Nacetylmuramoyl (MurNAc)–pentapeptide is synthesized in the cytosol. Second, this hydrophilic precursor is attached to a lipid carrier, and the complex lipid carrier-precursor is transported, through the membrane, to the periplasm. Third, the peptidoglycan precursors are polymerized to form the cell wall. MraY catalyzes the transfer of phospho-MurNAc-pentapeptide from hydrophilic substrate UDP-MurNAc-pentapeptide to the lipid carier (C55-P) in the presence of a Mg2+ cofactor. The product is the undecaprenyl-pyrophosphoryl-MurNAcpentapeptide, also known as lipid I <ref name="three"/> <ref name="seven">PMID:31266949</ref> <ref name="eight">PMID:18081839</ref>.
Peptidoglycan biosynthesis involves three main stages. MraY is responsible for the second stage. First, the peptidoglycan precursor UDP-Nacetylmuramoyl (MurNAc)–pentapeptide is synthesized in the cytosol. Second, this hydrophilic precursor is attached to a lipid carrier, and the complex lipid carrier-precursor is transported, through the membrane, to the periplasm. Third, the peptidoglycan precursors are polymerized to form the cell wall. MraY catalyzes the transfer of phospho-MurNAc-pentapeptide from hydrophilic substrate UDP-MurNAc-pentapeptide to the lipid carier (C55-P) in the presence of a Mg2+ cofactor. The product is the undecaprenyl-pyrophosphoryl-MurNAcpentapeptide, also known as lipid I <ref name="three"/> <ref name="seven">PMID:31266949</ref> <ref name="eight">PMID:18081839</ref>.
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== Structure ==
== Structure ==
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MraY is a '''membrane-bound enzyme''', for which the N and the C termini are located on the periplasmic side. This protein is made of four extracellular loops, five cytoplasmic loops (named A,B … and E) and ten transmembrane helices named TM1 to TM10. Though, TM9 is cleaved by a glycin residue into two helical segments named TM9a and TM9b. Furthermore, there is an additional helix between TM9b and TM10, which is only 11 residues long and is called TM9c. This helix contains a <scene name='42/421575/His_triad/1'>HHH motif</scene> (H290, 291 and 292) which plays a role in the enzyme’s substrat selectivity and is a part of the catalytic site <ref name="one">PMID:29778697</ref>. For example; they interact with tunicamycin and MD2. This small loop binds two Ni2+ ions, one on the two first histidines and the other one on the last one. Another part of this site is the residues corresponding to <scene name='42/421575/Asp117_and_asp118_which_are/1'>Asp117 and Asp118 which are involved in Mg2+coordination</scene> <ref name="four">PMID:29438582</ref>.TM5–TM10 and loops C and D also play a role in the catalytic site and contain many polar and charged amino acids residues <ref name="one">PMID:29778697</ref>. Also, some polar and charged amino acids on TM9b and loop E are pointing toward the active site, making it even more hydrophilic <ref name="four">PMID:29438582</ref>.
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<scene name='42/421575/Mray/1'>MraY</scene> is a '''membrane-bound enzyme''', for which the N and the C termini are located on the periplasmic side. This protein is made of four extracellular loops, five cytoplasmic loops (named A,B … and E) and ten transmembrane helices named TM1 to TM10. Though, TM9 is cleaved by a glycin residue into two helical segments named TM9a and TM9b. Furthermore, there is an additional helix between TM9b and TM10, which is only 11 residues long and is called TM9c. This helix contains a <scene name='42/421575/His_triad/1'>HHH motif</scene> (H290, 291 and 292) which plays a role in the enzyme’s substrat selectivity and is a part of the catalytic site <ref name="one">PMID:29778697</ref>. For example; they interact with tunicamycin and MD2. This small loop binds two Ni2+ ions, one on the two first histidines and the other one on the last one. Another part of this site is the residues corresponding to <scene name='42/421575/Asp117_and_asp118_which_are/1'>Asp117 and Asp118 which are involved in Mg2+coordination</scene> <ref name="four">PMID:29438582</ref>.TM5–TM10 and loops C and D also play a role in the catalytic site and contain many polar and charged amino acids residues <ref name="one">PMID:29778697</ref>. Also, some polar and charged amino acids on TM9b and loop E are pointing toward the active site, making it even more hydrophilic <ref name="four">PMID:29438582</ref>.
<scene name='42/421575/Carbacaprazamycin/1'>Carbacaprazamycin</scene> is made of uridine, 5-aminoribosyl, diazepanone, and aliphatic tail moieties. The diazepanone ring system makes relatively few interactions with the protein. Carbacapzazamycin contains an uridine binding pocket which is formed by amino acid residues in Loop C ( <scene name='42/421575/Binding_site/1'>G194, L195, and D196</scene>). This pocket is capped off by a π–π stacking interaction with <scene name='42/421575/Binding_site/1'>F262</scene> in Loop D. <scene name='42/421575/Binding_site/1'>K70</scene> forms an additional hydrogen bond with the uracil moiety. Next to the uridine binding site, there is a second binding pocket lined with amino acid residues<scene name='42/421575/Binding_site/1'> T75, N190, D193, and G264</scene>, called the uridine-adjacent pocket. The 5-aminoribose moiety of carbacaprazamycin forms an extensive hydrogen bond network in the uridine-adjacent pocket <ref name="seven">PMID:31266949</ref>.
<scene name='42/421575/Carbacaprazamycin/1'>Carbacaprazamycin</scene> is made of uridine, 5-aminoribosyl, diazepanone, and aliphatic tail moieties. The diazepanone ring system makes relatively few interactions with the protein. Carbacapzazamycin contains an uridine binding pocket which is formed by amino acid residues in Loop C ( <scene name='42/421575/Binding_site/1'>G194, L195, and D196</scene>). This pocket is capped off by a π–π stacking interaction with <scene name='42/421575/Binding_site/1'>F262</scene> in Loop D. <scene name='42/421575/Binding_site/1'>K70</scene> forms an additional hydrogen bond with the uracil moiety. Next to the uridine binding site, there is a second binding pocket lined with amino acid residues<scene name='42/421575/Binding_site/1'> T75, N190, D193, and G264</scene>, called the uridine-adjacent pocket. The 5-aminoribose moiety of carbacaprazamycin forms an extensive hydrogen bond network in the uridine-adjacent pocket <ref name="seven">PMID:31266949</ref>.

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Crystal structure of MraY bound to carbacaprazamycin

Crystal structure of MraY bound to carbacaprazamycin

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References

  1. ↑ 1.0 1.1 1.2 Hering J, Dunevall E, Ek M, Branden G. Structural basis for selective inhibition of antibacterial target MraY, a membrane-bound enzyme involved in peptidoglycan synthesis. Drug Discov Today. 2018 Jul;23(7):1426-1435. doi: 10.1016/j.drudis.2018.05.020., Epub 2018 May 18. PMID:29778697 doi:http://dx.doi.org/10.1016/j.drudis.2018.05.020
  2. ↑ 2.0 2.1 Koppermann S, Ducho C. Natural Products at Work: Structural Insights into Inhibition of the Bacterial Membrane Protein MraY. Angew Chem Int Ed Engl. 2016 Sep 19;55(39):11722-4. doi: 10.1002/anie.201606396. , Epub 2016 Aug 11. PMID:27511599 doi:http://dx.doi.org/10.1002/anie.201606396
  3. ↑ 3.0 3.1 3.2 Chung BC, Zhao J, Gillespie RA, Kwon DY, Guan Z, Hong J, Zhou P, Lee SY. Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. Science. 2013 Aug 30;341(6149):1012-6. doi: 10.1126/science.1236501. PMID:23990562 doi:10.1126/science.1236501
  4. ↑ 4.0 4.1 4.2 Koppermann S, Cui Z, Fischer PD, Wang X, Ludwig J, Thorson JS, Van Lanen SG, Ducho C. Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics. ChemMedChem. 2018 Apr 23;13(8):779-784. doi: 10.1002/cmdc.201700793. Epub 2018, Mar 23. PMID:29438582 doi:http://dx.doi.org/10.1002/cmdc.201700793
  5. ↑ Ichikawa S, Yamaguchi M, Hsuan LS, Kato Y, Matsuda A. Carbacaprazamycins: Chemically Stable Analogues of the Caprazamycin Nucleoside Antibiotics. ACS Infect Dis. 2015 Apr 10;1(4):151-6. doi: 10.1021/id5000376. Epub 2015 Feb 19. PMID:27622529 doi:http://dx.doi.org/10.1021/id5000376
  6. ↑ Aslam B, Wang W, Arshad MI, Khurshid M, Muzammil S, Rasool MH, Nisar MA, Alvi RF, Aslam MA, Qamar MU, Salamat MKF, Baloch Z. Antibiotic resistance: a rundown of a global crisis. Infect Drug Resist. 2018 Oct 10;11:1645-1658. doi: 10.2147/IDR.S173867., eCollection 2018. PMID:30349322 doi:http://dx.doi.org/10.2147/IDR.S173867
  7. ↑ 7.0 7.1 Winn M, Goss RJ, Kimura K, Bugg TD. Antimicrobial nucleoside antibiotics targeting cell wall assembly: recent advances in structure-function studies and nucleoside biosynthesis. Nat Prod Rep. 2010 Feb;27(2):279-304. doi: 10.1039/b816215h. Epub 2009 Dec 16. PMID:20111805 doi:http://dx.doi.org/10.1039/b816215h
  8. ↑ Romaniuk JA, Cegelski L. Bacterial cell wall composition and the influence of antibiotics by cell-wall and whole-cell NMR. Philos Trans R Soc Lond B Biol Sci. 2015 Oct 5;370(1679). pii: rstb.2015.0024., doi: 10.1098/rstb.2015.0024. PMID:26370936 doi:http://dx.doi.org/10.1098/rstb.2015.0024
  9. ↑ 9.0 9.1 Mashalidis EH, Kaeser B, Terasawa Y, Katsuyama A, Kwon DY, Lee K, Hong J, Ichikawa S, Lee SY. Chemical logic of MraY inhibition by antibacterial nucleoside natural products. Nat Commun. 2019 Jul 2;10(1):2917. doi: 10.1038/s41467-019-10957-9. PMID:31266949 doi:http://dx.doi.org/10.1038/s41467-019-10957-9
  10. ↑ Bouhss A, Trunkfield AE, Bugg TD, Mengin-Lecreulx D. The biosynthesis of peptidoglycan lipid-linked intermediates. FEMS Microbiol Rev. 2008 Mar;32(2):208-33. doi: 10.1111/j.1574-6976.2007.00089.x., Epub 2007 Dec 10. PMID:18081839 doi:http://dx.doi.org/10.1111/j.1574-6976.2007.00089.x
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