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Curcumin synthase

April 14, 2024

Curcumin synthase categorizes three enzyme isoforms (CURS1, 2, and 3), type III polyketide synthases (PKSs) present in the leaves and rhizome of the turmeric plant (Curcuma longa) [1] that synthesize curcumin.[2] CURS1-3 are responsible for the hydrolysis of feruloyldiketide-CoA,[3] previously produced in the curcuminoid pathway, and a decarboxylative condensation reaction[1][2] that together comprise one of the final steps in the synthesis pathway for curcumin, demethoxycurcumin, and bisdemethoxycurcumin, the compounds that give turmeric both its distinctive yellow color, and traditional medical benefits.[4] CURS should not be confused with Curcuminoid Synthase (CUS), which catalyzes the one-pot synthesis of bisdemethoxycurcumin in Oryza sativa.[5]

Curcumin synthase 1 (CURS1)
Identifiers
EC no.2.3.1.217
CAS no.1245303-08-5
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
Curcumin synthase 3 (CURS3)
Identifiers
EC no.2.3.1.219
CAS no.1245303-10-9
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

Structure edit

Crystallization studies [6] have determined that curcumin synthase is a homodimer of ketosynthase subunits.[2][7] Each includes a highly conserved Cys (164), His (303), Asn (336) catalytic triad, and CURS1 has been shown to exhibit the αβαβα folding pattern,[6] conserved features of type III PKSs.[7][8] The catalytic triads are independent of each other and are contained in the center of each monomer, connected to the surface with a CoA binding tunnel.[6] While CURS1, 2, and 3 share approximately 80% amino acid sequence identity, their small structural differences account for their differences in preferred starter substrates and most prolific product.[1]

The well conserved catalytic triad sits at the end of a hydrophobic cavity, referred to as the CoA binding tunnel, that allows for the specificity of curcumin synthase for the CoA moiety. The triad, displayed in a PyMOL image below, despite being buried in each monomer, is connected to the surface of the binding tunnel, allowing interactions with substrates. The pockets of the protein show this tunnel and where the β-keto acid tail of feruloyl-CoA can fit into, which we can also see in the photo of the CoA binding tunnel reaching towards the catalytic triad. In addition to the catalytic triad, there are two conserved phenylalanine residues, Phe-215 and Phe-265, and a glycine, Gly-211, that contribute to the nature of the hydrophobicity pocket. The phenylalanines are named the “gatekeepers,” which allow for the correct tunnel width for CoA. The Gyl-211 can be mutated to affect the trafficking of this pocket, as bulkier residues can occupy the hydrophobic cavity. CURS1 has not been crystallized with CoA, but chalcone synthase, which is another type III PKS, has been shown bound to CoA. CHS and curcumin synthase have the same catalytic triad and CoA binding tunnel, so we can look at the nature of binding. The CoA is held tightly in the CoA binding tunnel in the image of conserved residues, showing where it can connect to these gatekeepers and traffic guards of important residues.[6]

 
The Catalytic Triad of CURS1- Created in PyMol using PDB 3OV2, doi:10.1074/jbc.M110.196279
 
Conserved Residues with CoA Binding- Phe-215, Phe-265, and Gly-211 are shown surrounding the edges of the CoA binding tunnel. Curcumin synthase (PBD 3OV2) was aligned with chalcone synthase bound to CoA (PBD 1BQ6). CHS was hidden on PyMOL to reveal CoA binding with curcumin synthase.
 
CoA Binding Tunnel- The catalytic triad (shown in red) is connected to the CoA binding tunnel. Cavities and pockets of CURS1 were shown to show where CoA can connect to the catalytic triad (PBD 3OV2).

Mechanism edit

Each CURS catalyzes the reactions necessary to convert a feruloyldiketide-CoA into a curcuminoid, but the three isoforms have preferred starter substrates and products. CURS1 converts feruloyldiketide-CoA esters into curcumin using feruloyl-CoA exclusively as a starter substrate. CURS2 produces both curcumin and demethoxycurcumin, favoring feruloyl-CoA as a starter, and CURS3 produces curcumin, demethoxycurcumin, and bisdemethoxycurcumin from either feruloyl-CoA or 4-coumaroyl-CoA as the starter substrate.[3] The fact that preferences of starter substrates vary between the three CURS is corroborated by carbon labeling studies confirming the incorporation of a variety of starter substrates into curcuminoid products in C. longa.[9]

Only the mechanism of CURS1 has been elucidated. In the first step, the feruloyl moiety of feruloyl-CoA is transferred to Cys (164) followed by feruloyldiketide-CoA entering the CoA binding tunnel and being hydrolyzed through an unknown mechanism to a β-keto acid.[6] The acid is then used as an extender substrate in the catalytic triad, where it undergoes decarboxylative condensation with the feruloyl moiety on Cys (164). This mechanism is thought to be identical to that of the decarboxylative condensation of malonyl-CoA in other type III PKSs.[6] The hydrolysis of the diketide has been shown to be the rate-limiting step of the enzyme.[6]

It was previously hypothesized that the curcumoid pathway employed two cinnamoyl-CoAs and one malonyl-CoA, but this was suggested against by the absence of a necessary intermediate such a pathway (bisdeshydroxybisdesmethoxycurcumin),[9] strengthening evidence for feruloyl-CoA or 4-coumaroyl-CoA as starter substrate in CURS.

Biological activity edit

The production of curcumin and its derivatives by CURS may be a defense mechanism of C. longa against internal and external threats. Curcumin is a potent antioxidant, as its phenolic structure, highest in activity in curcumin rather than its demethoxylated derivatives,[10] acts as a free-radical scavenging apparatus, eliminating free superoxides and DPPH from the plant's cells.[10] Curcumin synthase may also protect Curcuma longa from herbivores to some degree, as curcumin has a distinctively bitter taste:[10] studies show CURS1, 2 have higher expression in the leaves of C. longa than the rhizome [1][11] while CURS3 shows equal expression in both locations.[1]

Role in cancer research edit

Research suggests that curcumin is an active anti-cancer molecule against cancers of brain, breast, bones, blood, gastrointestinal tract, genitourinary tract, as well as thoracic and gynecological cancers.[12] The molecule achieves this wide-range activity by up or down-regulating numerous receptors, kinases, growth factors, transcriptional factors, and inflammatory cytokines, among others,[12] thus its biosynthesis is of great interest to medicine.

 
The Proposed Mechanism of CURS1-Original work using ChemBioDraw. Based upon the mechanism elucidated in doi:10.1074/jbc.M110.196279

For instance, curcumin inhibits mammalian nuclear factor κB (NF-κB) by preventing its translocation to the nucleus.[10] This inhibitory action upregulates the levels of preapoptotic and apoptotic cells, eliminating damaged cells, and discouraging abnormal growth patterns, as well as decreasing chemokine levels.[13] As activated NF-κB is associated with oxidative stress,[13] inhibition of the nuclear factor by curcumin is consistent with the chemical's role as an antioxidant. A homologous system to NF-κB signaling exists in plants,[14] evidence that curcumin may play a similar role in C. longa as it does in humans.

Curcumin syntheses in C. longa have been until recently, the only readily available synthesis method of curcumin. Today, laboratory syntheses are capable of producing the chemical,[15] and numerous teams are constructing curcumin analogues designed to target specific biological processes, such as the NFκB signaling pathway previously discussed.[16]

References edit

  1. ^ a b c d e Katsuyama Y, Kita T, Horinouchi S (September 2009). "Identification and characterization of multiple curcumin synthases from the herb Curcuma longa". FEBS Letters. 583 (17): 2799–803. doi:10.1016/j.febslet.2009.07.029. PMID 19622354. S2CID 21516172.
  2. ^ a b c Katsuyama Y, Kita T, Funa N, Horinouchi S (April 2009). "Curcuminoid biosynthesis by two type III polyketide synthases in the herb Curcuma longa". The Journal of Biological Chemistry. 284 (17): 11160–70. doi:10.1074/jbc.M900070200. PMC 2670121. PMID 19258320.
  3. ^ a b Yu D, Xu F, Zeng J, Zhan J (April 2012). "Type III polyketide synthases in natural product biosynthesis". IUBMB Life. 64 (4): 285–95. doi:10.1002/iub.1005. PMID 22362498. S2CID 205967300.
  4. ^ Nair KP (2013). The Agronomy and Economy of Turmeric and Ginger: The Invaluable Medicinal Spice Crops. Oxford: Elsevier. ISBN 978-0-12-394801-4.
  5. ^ Katsuyama Y, Matsuzawa M, Funa N, Horinouchi S (December 2007). "In vitro synthesis of curcuminoids by type III polyketide synthase from Oryza sativa". The Journal of Biological Chemistry. 282 (52): 37702–9. doi:10.1074/jbc.M707569200. PMID 17932040.
  6. ^ a b c d e f g Katsuyama Y, Miyazono K, Tanokura M, Ohnishi Y, Horinouchi S (February 2011). "Structural and biochemical elucidation of mechanism for decarboxylative condensation of beta-keto acid by curcumin synthase". The Journal of Biological Chemistry. 286 (8): 6659–68. doi:10.1074/jbc.M110.196279. PMC 3057783. PMID 21148316.
  7. ^ a b Jez JM, Ferrer JL, Bowman ME, Austin MB, Schröder J, Dixon RA, Noel JP (2001). "Structure and mechanism of chalcone synthase-like polyketide synthases". Journal of Industrial Microbiology and Biotechnology. 27 (6): 393–398. doi:10.1038/sj.jim.7000188. PMID 11774005. S2CID 22580876.
  8. ^ Austin MB, Noel JP (February 2003). "The chalcone synthase superfamily of type III polyketide synthases". Natural Product Reports. 20 (1): 79–110. CiteSeerX 10.1.1.131.8158. doi:10.1039/B100917F. PMID 12636085.
  9. ^ a b Kita T, Imai S, Sawada H, Kumagai H, Seto H (July 2008). "The biosynthetic pathway of curcuminoid in turmeric (Curcuma longa) as revealed by 13C-labeled precursors". Bioscience, Biotechnology, and Biochemistry. 72 (7): 1789–98. doi:10.1271/bbb.80075. PMID 18603793.
  10. ^ a b c d Esatbeyoglu T, Huebbe P, Ernst IM, Chin D, Wagner AE, Rimbach G (May 2012). "Curcumin--from molecule to biological function". Angewandte Chemie. 51 (22): 5308–32. doi:10.1002/anie.201107724. PMID 22566109.
  11. ^ Ramirez-Ahumada Mdel C, Timmermann BN, Gang DR (September 2006). "Biosynthesis of curcuminoids and gingerols in turmeric (Curcuma longa) and ginger (Zingiber officinale): identification of curcuminoid synthase and hydroxycinnamoyl-CoA thioesterases". Phytochemistry. 67 (18): 2017–29. doi:10.1016/j.phytochem.2006.06.028. PMID 16890967.
  12. ^ a b Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB (August 2008). "Curcumin and cancer: an "old-age" disease with an "age-old" solution". Cancer Letters. 267 (1): 133–64. doi:10.1016/j.canlet.2008.03.025. PMID 18462866.
  13. ^ a b Caamaño J, Hunter CA (July 2002). "NF-kappaB family of transcription factors: central regulators of innate and adaptive immune functions". Clinical Microbiology Reviews. 15 (3): 414–29. doi:10.1128/CMR.15.3.414-429.2002. PMC 118079. PMID 12097249.
  14. ^ Zhang G, Ghosh S (January 2001). "Toll-like receptor-mediated NF-kappaB activation: a phylogenetically conserved paradigm in innate immunity". The Journal of Clinical Investigation. 107 (1): 13–9. doi:10.1172/JCI11837. PMC 198554. PMID 11134172.
  15. ^ Babu KV, Rajasekharan KN (1994). "Simplified Condition for Synthesis of Curcumin I and Other Curcuminoids". Organic Preparations and Procedures International. 26 (6): 674–677. doi:10.1080/00304949409458165.
  16. ^ Qiu X, Du Y, Lou B, Zuo Y, Shao W, Huo Y, Huang J, Yu Y, Zhou B, Du J, Fu H, Bu X (December 2010). "Synthesis and identification of new 4-arylidene curcumin analogues as potential anticancer agents targeting nuclear factor-κB signaling pathway". Journal of Medicinal Chemistry. 53 (23): 8260–73. doi:10.1021/jm1004545. PMC 3990230. PMID 21070043.

April 14, 2024
curcumin, synthase, categorizes, three, enzyme, isoforms, curs1, type, polyketide, synthases, pkss, present, leaves, rhizome, turmeric, plant, curcuma, longa, that, synthesize, curcumin, curs1, responsible, hydrolysis, feruloyldiketide, previously, produced, c. Curcumin synthase categorizes three enzyme isoforms CURS1 2 and 3 type III polyketide synthases PKSs present in the leaves and rhizome of the turmeric plant Curcuma longa 1 that synthesize curcumin 2 CURS1 3 are responsible for the hydrolysis of feruloyldiketide CoA 3 previously produced in the curcuminoid pathway and a decarboxylative condensation reaction 1 2 that together comprise one of the final steps in the synthesis pathway for curcumin demethoxycurcumin and bisdemethoxycurcumin the compounds that give turmeric both its distinctive yellow color and traditional medical benefits 4 CURS should not be confused with Curcuminoid Synthase CUS which catalyzes the one pot synthesis of bisdemethoxycurcumin in Oryza sativa 5 Curcumin synthase 1 CURS1 IdentifiersEC no 2 3 1 217CAS no 1245303 08 5DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumGene OntologyAmiGO QuickGOSearchPMCarticlesPubMedarticlesNCBIproteinsCurcumin synthase 3 CURS3 IdentifiersEC no 2 3 1 219CAS no 1245303 10 9DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumGene OntologyAmiGO QuickGOSearchPMCarticlesPubMedarticlesNCBIproteins Contents 1 Structure 2 Mechanism 3 Biological activity 4 Role in cancer research 5 ReferencesStructure editCrystallization studies 6 have determined that curcumin synthase is a homodimer of ketosynthase subunits 2 7 Each includes a highly conserved Cys 164 His 303 Asn 336 catalytic triad and CURS1 has been shown to exhibit the ababa folding pattern 6 conserved features of type III PKSs 7 8 The catalytic triads are independent of each other and are contained in the center of each monomer connected to the surface with a CoA binding tunnel 6 While CURS1 2 and 3 share approximately 80 amino acid sequence identity their small structural differences account for their differences in preferred starter substrates and most prolific product 1 The well conserved catalytic triad sits at the end of a hydrophobic cavity referred to as the CoA binding tunnel that allows for the specificity of curcumin synthase for the CoA moiety The triad displayed in a PyMOL image below despite being buried in each monomer is connected to the surface of the binding tunnel allowing interactions with substrates The pockets of the protein show this tunnel and where the b keto acid tail of feruloyl CoA can fit into which we can also see in the photo of the CoA binding tunnel reaching towards the catalytic triad In addition to the catalytic triad there are two conserved phenylalanine residues Phe 215 and Phe 265 and a glycine Gly 211 that contribute to the nature of the hydrophobicity pocket The phenylalanines are named the gatekeepers which allow for the correct tunnel width for CoA The Gyl 211 can be mutated to affect the trafficking of this pocket as bulkier residues can occupy the hydrophobic cavity CURS1 has not been crystallized with CoA but chalcone synthase which is another type III PKS has been shown bound to CoA CHS and curcumin synthase have the same catalytic triad and CoA binding tunnel so we can look at the nature of binding The CoA is held tightly in the CoA binding tunnel in the image of conserved residues showing where it can connect to these gatekeepers and traffic guards of important residues 6 nbsp The Catalytic Triad of CURS1 Created in PyMol using PDB 3OV2 doi 10 1074 jbc M110 196279 nbsp Conserved Residues with CoA Binding Phe 215 Phe 265 and Gly 211 are shown surrounding the edges of the CoA binding tunnel Curcumin synthase PBD 3OV2 was aligned with chalcone synthase bound to CoA PBD 1BQ6 CHS was hidden on PyMOL to reveal CoA binding with curcumin synthase nbsp CoA Binding Tunnel The catalytic triad shown in red is connected to the CoA binding tunnel Cavities and pockets of CURS1 were shown to show where CoA can connect to the catalytic triad PBD 3OV2 Mechanism editEach CURS catalyzes the reactions necessary to convert a feruloyldiketide CoA into a curcuminoid but the three isoforms have preferred starter substrates and products CURS1 converts feruloyldiketide CoA esters into curcumin using feruloyl CoA exclusively as a starter substrate CURS2 produces both curcumin and demethoxycurcumin favoring feruloyl CoA as a starter and CURS3 produces curcumin demethoxycurcumin and bisdemethoxycurcumin from either feruloyl CoA or 4 coumaroyl CoA as the starter substrate 3 The fact that preferences of starter substrates vary between the three CURS is corroborated by carbon labeling studies confirming the incorporation of a variety of starter substrates into curcuminoid products in C longa 9 Only the mechanism of CURS1 has been elucidated In the first step the feruloyl moiety of feruloyl CoA is transferred to Cys 164 followed by feruloyldiketide CoA entering the CoA binding tunnel and being hydrolyzed through an unknown mechanism to a b keto acid 6 The acid is then used as an extender substrate in the catalytic triad where it undergoes decarboxylative condensation with the feruloyl moiety on Cys 164 This mechanism is thought to be identical to that of the decarboxylative condensation of malonyl CoA in other type III PKSs 6 The hydrolysis of the diketide has been shown to be the rate limiting step of the enzyme 6 It was previously hypothesized that the curcumoid pathway employed two cinnamoyl CoAs and one malonyl CoA but this was suggested against by the absence of a necessary intermediate such a pathway bisdeshydroxybisdesmethoxycurcumin 9 strengthening evidence for feruloyl CoA or 4 coumaroyl CoA as starter substrate in CURS Biological activity editThe production of curcumin and its derivatives by CURS may be a defense mechanism of C longa against internal and external threats Curcumin is a potent antioxidant as its phenolic structure highest in activity in curcumin rather than its demethoxylated derivatives 10 acts as a free radical scavenging apparatus eliminating free superoxides and DPPH from the plant s cells 10 Curcumin synthase may also protect Curcuma longa from herbivores to some degree as curcumin has a distinctively bitter taste 10 studies show CURS1 2 have higher expression in the leaves of C longa than the rhizome 1 11 while CURS3 shows equal expression in both locations 1 Role in cancer research editResearch suggests that curcumin is an active anti cancer molecule against cancers of brain breast bones blood gastrointestinal tract genitourinary tract as well as thoracic and gynecological cancers 12 The molecule achieves this wide range activity by up or down regulating numerous receptors kinases growth factors transcriptional factors and inflammatory cytokines among others 12 thus its biosynthesis is of great interest to medicine nbsp The Proposed Mechanism of CURS1 Original work using ChemBioDraw Based upon the mechanism elucidated in doi 10 1074 jbc M110 196279For instance curcumin inhibits mammalian nuclear factor kB NF kB by preventing its translocation to the nucleus 10 This inhibitory action upregulates the levels of preapoptotic and apoptotic cells eliminating damaged cells and discouraging abnormal growth patterns as well as decreasing chemokine levels 13 As activated NF kB is associated with oxidative stress 13 inhibition of the nuclear factor by curcumin is consistent with the chemical s role as an antioxidant A homologous system to NF kB signaling exists in plants 14 evidence that curcumin may play a similar role in C longa as it does in humans Curcumin syntheses in C longa have been until recently the only readily available synthesis method of curcumin Today laboratory syntheses are capable of producing the chemical 15 and numerous teams are constructing curcumin analogues designed to target specific biological processes such as the NFkB signaling pathway previously discussed 16 References edit a b c d e Katsuyama Y Kita T Horinouchi S September 2009 Identification and characterization of multiple curcumin synthases from the herb Curcuma longa FEBS Letters 583 17 2799 803 doi 10 1016 j febslet 2009 07 029 PMID 19622354 S2CID 21516172 a b c Katsuyama Y Kita T Funa N Horinouchi S April 2009 Curcuminoid biosynthesis by two type III polyketide synthases in the herb Curcuma longa The Journal of Biological Chemistry 284 17 11160 70 doi 10 1074 jbc M900070200 PMC 2670121 PMID 19258320 a b Yu D Xu F Zeng J Zhan J April 2012 Type III polyketide synthases in natural product biosynthesis IUBMB Life 64 4 285 95 doi 10 1002 iub 1005 PMID 22362498 S2CID 205967300 Nair KP 2013 The Agronomy and Economy of Turmeric and Ginger The Invaluable Medicinal Spice Crops Oxford Elsevier ISBN 978 0 12 394801 4 Katsuyama Y Matsuzawa M Funa N Horinouchi S December 2007 In vitro synthesis of curcuminoids by type III polyketide synthase from Oryza sativa The Journal of Biological Chemistry 282 52 37702 9 doi 10 1074 jbc M707569200 PMID 17932040 a b c d e f g Katsuyama Y Miyazono K Tanokura M Ohnishi Y Horinouchi S February 2011 Structural and biochemical elucidation of mechanism for decarboxylative condensation of beta keto acid by curcumin synthase The Journal of Biological Chemistry 286 8 6659 68 doi 10 1074 jbc M110 196279 PMC 3057783 PMID 21148316 a b Jez JM Ferrer JL Bowman ME Austin MB Schroder J Dixon RA Noel JP 2001 Structure and mechanism of chalcone synthase like polyketide synthases Journal of Industrial Microbiology and Biotechnology 27 6 393 398 doi 10 1038 sj jim 7000188 PMID 11774005 S2CID 22580876 Austin MB Noel JP February 2003 The chalcone synthase superfamily of type III polyketide synthases Natural Product Reports 20 1 79 110 CiteSeerX 10 1 1 131 8158 doi 10 1039 B100917F PMID 12636085 a b Kita T Imai S Sawada H Kumagai H Seto H July 2008 The biosynthetic pathway of curcuminoid in turmeric Curcuma longa as revealed by 13C labeled precursors Bioscience Biotechnology and Biochemistry 72 7 1789 98 doi 10 1271 bbb 80075 PMID 18603793 a b c d Esatbeyoglu T Huebbe P Ernst IM Chin D Wagner AE Rimbach G May 2012 Curcumin from molecule to biological function Angewandte Chemie 51 22 5308 32 doi 10 1002 anie 201107724 PMID 22566109 Ramirez Ahumada Mdel C Timmermann BN Gang DR September 2006 Biosynthesis of curcuminoids and gingerols in turmeric Curcuma longa and ginger Zingiber officinale identification of curcuminoid synthase and hydroxycinnamoyl CoA thioesterases Phytochemistry 67 18 2017 29 doi 10 1016 j phytochem 2006 06 028 PMID 16890967 a b Anand P Sundaram C Jhurani S Kunnumakkara AB Aggarwal BB August 2008 Curcumin and cancer an old age disease with an age old solution Cancer Letters 267 1 133 64 doi 10 1016 j canlet 2008 03 025 PMID 18462866 a b Caamano J Hunter CA July 2002 NF kappaB family of transcription factors central regulators of innate and adaptive immune functions Clinical Microbiology Reviews 15 3 414 29 doi 10 1128 CMR 15 3 414 429 2002 PMC 118079 PMID 12097249 Zhang G Ghosh S January 2001 Toll like receptor mediated NF kappaB activation a phylogenetically conserved paradigm in innate immunity The Journal of Clinical Investigation 107 1 13 9 doi 10 1172 JCI11837 PMC 198554 PMID 11134172 Babu KV Rajasekharan KN 1994 Simplified Condition for Synthesis of Curcumin I and Other Curcuminoids Organic Preparations and Procedures International 26 6 674 677 doi 10 1080 00304949409458165 Qiu X Du Y Lou B Zuo Y Shao W Huo Y Huang J Yu Y Zhou B Du J Fu H Bu X December 2010 Synthesis and identification of new 4 arylidene curcumin analogues as potential anticancer agents targeting nuclear factor kB signaling pathway Journal of Medicinal Chemistry 53 23 8260 73 doi 10 1021 jm1004545 PMC 3990230 PMID 21070043 Portal nbsp Biology Retrieved from https en wikipedia org w index php title Curcumin synthase amp oldid 1170109332, wikipedia, wiki, book, books, library,

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