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This subpathway is part of the pathway staphyloxanthin biosynthesis, which is itself part of carotenoid biosynthesis. Carotenoid pathways are branches of the general isoprenoid pathway. | This subpathway is part of the pathway staphyloxanthin biosynthesis, which is itself part of carotenoid biosynthesis. Carotenoid pathways are branches of the general isoprenoid pathway. | ||
| - | Staphyloxanthin is a carotenoid, which is responsible for the golden color of | + | Staphyloxanthin is a carotenoid, which is responsible for the signature golden color of ''Staphylococcus aureus'', which also plays the role of virulence factor. It has an antioxidant action that helps the microbe evade death by reactive oxygen species produced by the host immune system. Having a better comprehension of the synthesis of this carotenoid will help to find a cure to ''S. aureus'' related diseases. {{cn}} |
(The dehydrosqualene (C30 carotene) synthase CrtM is a bacterial carotenoid synthase which is involved in staphyloxanthin synthesis in ''Staphylococcus aureus''.{{cn}}) | (The dehydrosqualene (C30 carotene) synthase CrtM is a bacterial carotenoid synthase which is involved in staphyloxanthin synthesis in ''Staphylococcus aureus''.{{cn}}) | ||
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== Biological process == | == Biological process == | ||
| - | CrtM catalyses the first step of the synthesis of staphyloxanthin (with a 2-step mechanism)<ref | + | CrtM catalyses the first step of the synthesis of staphyloxanthin (with a 2-step mechanism)<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1539600/]Alexandra Clauditz, Alexandra Resch, Karsten-Peter Wieland, Andreas Peschel, and Friedrich Götz. Staphyloxanthin Plays a Role in the Fitness of Staphylococcus aureus and Its Ability To Cope with Oxidative Stress. Infect Immun. 2006 Aug; 74(8): 4950–4953. doi: 10.1128/IAI.00204-06 PMCID: PMC1539600{{PMID|16861688}}</ref>. The gene is located in the staphyloxanthin biosynthesis operon (operon ''crtOPQMN''), which encodes enzymes to catalyze the synthesis<ref>[http://www.jbc.org/content/280/37/32493.long]Pelz A, Wieland KP, Putzbach K, Hentschel P, Albert K, Götz F. Structure and biosynthesis of staphyloxanthin from Staphylococcus aureus. J Biol Chem. 2005 Sep 16;280(37):32493-8. Epub 2005 Jul 14. {{PMID|16020541}}</ref>. |
| - | The | + | ; Catalysed reaction |
| + | : 2 (2E,6E)-farnesyl diphosphate ↔15-cis-4,4'-diapophytoene + 2 diphosphate | ||
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Contents |
Presentation of dehydrosqualene synthase(Function)
The C30 carotene synthase CrtM enzyme is a bacterial carotenoid synthases which is involved in the first step of the subpathway that synthesizes staphyloxanthin from farnesyl diphosphate.
This subpathway is part of the pathway staphyloxanthin biosynthesis, which is itself part of carotenoid biosynthesis. Carotenoid pathways are branches of the general isoprenoid pathway.
Staphyloxanthin is a carotenoid, which is responsible for the signature golden color of Staphylococcus aureus, which also plays the role of virulence factor. It has an antioxidant action that helps the microbe evade death by reactive oxygen species produced by the host immune system. Having a better comprehension of the synthesis of this carotenoid will help to find a cure to S. aureus related diseases. Template:Cn
(The dehydrosqualene (C30 carotene) synthase CrtM is a bacterial carotenoid synthase which is involved in staphyloxanthin synthesis in Staphylococcus aureus.Template:Cn)
Function(Reaction)
Catalyzes the head-to-head condensation of two molecules of farnesyl diphosphate (FPP) into the colorless C(30) carotenoid 4,4'-diapophytoene (dehydrosqualene).Template:Cn
Transferase Activity : Transferring alkyl or aryl groups, other than methyl groups
Metal Ion Binding : requires Mn2+ as cofactor (2 ions per subunit).
Structure
This enzyme consists of 2 sequence-identical polypeptide chains of 287 amino acids[1].
- Ligands
- 6 Magnesium ions
- 2 PO42-
- 1 L(+)-tartaric acid
- 2 (3r)-3-biphenyl-4-yl-1-azabicyclo[2.2.2]octan-3-ol
Structures of BPH-651, a 3-OH quinuclidine inhibitor, bound to CrtM
The space group of FsPP·CrtM is P3121, with two molecules per asymmetric unit[2]. Three phosphonosulfonates, which mimic the FPP substract have been identified to have binding/inhibiting activity on CrtM, each with different binding pattern.
Biological process
CrtM catalyses the first step of the synthesis of staphyloxanthin (with a 2-step mechanism)[3]. The gene is located in the staphyloxanthin biosynthesis operon (operon crtOPQMN), which encodes enzymes to catalyze the synthesis[4].
- Catalysed reaction
- 2 (2E,6E)-farnesyl diphosphate ↔15-cis-4,4'-diapophytoene + 2 diphosphate
Relevance to diseases
The Staphyloxanthin catalyzed by CrtM is a virulence factor linked with infections caused by methicillin-resistant Staphylococcus aureus (MRSA) [5]. Due to its structure similiance as well as shared inhibitor with human squalene synthase (SQS), it is seen as a potential target for virulence factor neutralization therapy, which might reduce the death rate caused by antibiotic resistant bacteria infection. Cationic inhibitors are here of interest as anti-infectives because they can substitute themselves to Mg2+ and inactivate the enzyme.
References
- ↑ [1]StrainVijay Aswani, Bob Mau, and Sanjay K. Shukla. Complete Genome Sequence of Staphylococcus aureus MCRF184, a Necrotizing Fasciitis-Causing Methicillin-Sensitive Sequence Type 45 Staphylococcus. Genome Announc. 2016 May-Jun; 4(3): e00374-16. Published online 2016 May 12. doi: 10.1128/genomeA.00374-16 PMCID: PMC4866860 PubMed:27174283
- ↑ [2]Chia-I Liu, George Y. Liu, Yongcheng Song, Fenglin Yin, Mary E. Hensler, Wen-Yin Jeng, Victor Nizet, Andrew H.-J. Wang, and Eric Oldfield. A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence. Science. 2008 Mar 7; 319(5868): 1391–1394. Published online 2008 Feb 14. : 10.1126/science.1153018. PMCID: PMC2747771 NIHMSID: NIHMS137229 PubMed:18276850.
- ↑ [3]Alexandra Clauditz, Alexandra Resch, Karsten-Peter Wieland, Andreas Peschel, and Friedrich Götz. Staphyloxanthin Plays a Role in the Fitness of Staphylococcus aureus and Its Ability To Cope with Oxidative Stress. Infect Immun. 2006 Aug; 74(8): 4950–4953. doi: 10.1128/IAI.00204-06 PMCID: PMC1539600PubMed:16861688
- ↑ [4]Pelz A, Wieland KP, Putzbach K, Hentschel P, Albert K, Götz F. Structure and biosynthesis of staphyloxanthin from Staphylococcus aureus. J Biol Chem. 2005 Sep 16;280(37):32493-8. Epub 2005 Jul 14. PubMed:16020541
- ↑ [5]Klevens RM1, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, Harrison LH, Lynfield R, Dumyati G, Townes JM, Craig AS, Zell ER, Fosheim GE, McDougal LK, Carey RB, Fridkin SK; Active Bacterial Core surveillance (ABCs) MRSA Investigators. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA. 2007 Oct 17;298(15):1763-71. PubMed:17940231 doi:10.1001/jama.298.15.1763
