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<Structure load='4ea0' size='350' frame='true' align='right' caption='Dehydrosqualene synthase complexed with diphosphate and quinuclidine BPH-651' scene='Insert optional scene name here' />
<Structure load='4ea0' size='350' frame='true' align='right' caption='Dehydrosqualene synthase complexed with diphosphate and quinuclidine BPH-651' scene='Insert optional scene name here' />
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== Presentation of dehydrosqualene synthase ==
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== Presentation of dehydrosqualene synthase(Function) ==
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The C30 carotene synthase CrtM enzyme is a bacterial carotenoid synthases and is involved in the first step of the subpathway that synthesizes staphyloxanthin from farnesyl diphosphate.
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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.
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.
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Staphyloxanthin is a carotenoid, which is responsible for the golden color of S. aureus, and also play 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.
Staphyloxanthin is a carotenoid, which is responsible for the golden color of S. aureus, and also play 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.
 +
(The dehydrosqualene (C30 carotene) synthase CrtM is a bacterial carotenoid synthase which is involved in staphyloxanthin synthesis in ''Staphylococcus aureus''.
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== Function ==
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This subpathway is part of the pathway staphyloxanthin biosynthesis, which is itself part of carotenoid biosynthesis, which is again a branch of the general isoprenoid pathway.
 +
 
 +
 
 +
== 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).
Catalyzes the head-to-head condensation of two molecules of farnesyl diphosphate (FPP) into the colorless C(30) carotenoid 4,4'-diapophytoene (dehydrosqualene).
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== Biological process ==
== Biological process ==
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CrtM catalyses the first step of the synthesis of staphyloxanthin (with a 2-step mechanism).
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(3) CrtM catalyses the first step of the synthesis of staphyloxanthin (with a 2-step mechanism).
The catalysed reaction is : 2 (2E,6E)-farnesyl diphosphate <=> 15-cis-4,4'-diapophytoene + 2 diphosphate
The catalysed reaction is : 2 (2E,6E)-farnesyl diphosphate <=> 15-cis-4,4'-diapophytoene + 2 diphosphate
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== Disease ==
== Disease ==
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This enzyme has a role to play in pathogenesis, according to the fact that staphyloxanthin is a virulence factor.
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This enzyme has a role to play in pathogenesis, according to the fact that staphyloxanthin is a virulence factor. (1) infections with methicillin-resistant Staphylococcus aureus (MRSA)
== Relevance ==
== Relevance ==
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== References ==
== References ==
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 +
1. 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. PMID: 17940231 doi:10.1001/jama.298.15.1763
 +
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.
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Published online 2008 Feb 14. : 10.1126/science.1153018. PMCID: PMC2747771 NIHMSID: NIHMS137229 PMID: 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: PMC1539600 PMID: 16861688

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Dehydrosqualene synthase complexed with diphosphate and quinuclidine BPH-651

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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 golden color of S. aureus, and also play 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.

(The dehydrosqualene (C30 carotene) synthase CrtM is a bacterial carotenoid synthase which is involved in staphyloxanthin synthesis in Staphylococcus aureus.

This subpathway is part of the pathway staphyloxanthin biosynthesis, which is itself part of carotenoid biosynthesis, which is again a branch of the general isoprenoid pathway.


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).

Image:CrtMcatalysa.png

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. Ligands : 6 Magnesium ions, 2 Pyrophosphate 2-, 1 L(+)-tartaric acid and 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

Image:Quinucli.jpg

Biological process

(3) CrtM catalyses the first step of the synthesis of staphyloxanthin (with a 2-step mechanism). The catalysed reaction is : 2 (2E,6E)-farnesyl diphosphate <=> 15-cis-4,4'-diapophytoene + 2 diphosphate



Disease

This enzyme has a role to play in pathogenesis, according to the fact that staphyloxanthin is a virulence factor. (1) infections with methicillin-resistant Staphylococcus aureus (MRSA)

Relevance

Inhibiting the formation of staphyloxanthin is of interest in the context of developing new routes to antiinfective therapies. Cationic inhibitors are here of interest as antiinfectives because they can substitute themselves to Mg2+ and inactivate the enzyme.

References

1. 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. PMID: 17940231 doi:10.1001/jama.298.15.1763 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 PMID: 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: PMC1539600 PMID: 16861688

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