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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2014, Vol. 8 Issue (3) : 285-293     DOI: 10.1007/s11684-014-0350-2
REVIEW |
Biosynthetic pathway of terpenoid indole alkaloids in Catharanthus roseus
Xiaoxuan Zhu1,Xinyi Zeng1,Chao Sun1,*(),Shilin Chen2,*()
1. Institute of Medicinal Plant Development, China Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China
2. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
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Abstract  

Catharanthus roseus is one of the most extensively investigated medicinal plants, which can produce more than 130 alkaloids, including the powerful antitumor drugs vinblastine and vincristine. Here we review the recent advances in the biosynthetic pathway of terpenoid indole alkaloids (TIAs) in C. roseus, and the identification and characterization of the corresponding enzymes involved in this pathway. Strictosidine is the central intermediate in the biosynthesis of different TIAs, which is formed by the condensation of secologanin and tryptamine. Secologanin is derived from terpenoid (isoprenoid) biosynthetic pathway, while tryptamine is derived from indole biosynthetic pathway. Then various specific end products are produced by different routes during downstream process. Although many genes and corresponding enzymes have been characterized in this pathway, our knowledge on the whole TIA biosynthetic pathway still remains largely unknown up to date. Full elucidation of TIA biosynthetic pathway is an important prerequisite to understand the regulation of the TIA biosynthesis in the medicinal plant and to produce valuable TIAs by synthetic biological technology.

Keywords Catharanthus roseus      terpenoidindole alkaloids      biosynthetic pathway      vinblastine      vincristine     
Corresponding Authors: Chao Sun   
Online First Date: 25 August 2014    Issue Date: 09 October 2014
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-014-0350-2     OR     http://academic.hep.com.cn/fmd/EN/Y2014/V8/I3/285
Fig.1  An overview of the pathways leading to TIAs biosynthesis. Solid arrows indicate one-step reaction; dashed arrows indicate uncharacterized steps; white arrows indicate multi-step reactions.
Fig.2  The biosynthesis of IPP via MVA pathway and MEP pathway. Abbreviations: AACT: acetoacetyl-CoA thiolase; HMGS: hydroxymethyglutaryl-CoA synthase; HMGR: hydroxymethyglutaryl-CoA reductase; MVK: mevalonate kinase; PMK: mevalonate 5-phosphate kinase; MVD: mevalonate 5-diphosphate decarboxylase; DXS: 1-deoxy-D-xylulose-5-phosphate synthase; DXR: 1-deoxy-D-xylulose-5-phosphate reductoisomerase; CMS: 4-diphosphocytidyl-2-C-methyl-D-erythritol synthase; CMK: 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase; MECS: 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase; HDS: 1-hydroxy-2-methyl-2-butenyl 4-diphosphate synthase; HDR: 1-hydroxy-2-methyl-2-butenyl 4-diphosphate reductase; IDI: isopentenyldiphosphateisomerase.
Fig.3  The biosynthesis of secologanin from GPP. Abbreviations: G10H: geraniol 10-hydroxylase; 10-HGO: 10-hydroxygeraniol oxidoreductase; IRS: iridoid synthase; 7DLS: 7-deoxyloganetic acid synthase; DLGT: 7-deoxyloganetic acid glucosyltransferase; DL7H: 7-deoxyloganic acid 7-hydroxylase; LAMT: loganic acid O-methyltransferase; SLS: secologanin synthase.
Names of enzymeA Abbreviations AbbreviationsAccession numbersReferences
Hydroxymethylglutaryl-CoA reductaseHMGRM96068.1[14]
Mevalonate kinaseMVKHM462019.1[19]
Mevalonate 5-phosphate kinasePMKHM462020.1[19]
Mevalonate 5-diphosphate decarboxylaseMVDHM462021.1[19]
IsopentenyldiphosphateisomeraseIDIEU135981.1[20]
1-deoxy-D-xylulose-5-phosphate synthaseDXSKC625536.1; DQ848672.1; AJ011840.2[9,21]
1-deoxy-D-xylulose-5-phosphate reductoisomeraseDXRAF250235.1[22]
4-diphosphocytidyl-2-C-methyl-D-erythritol kinaseCMKDQ848671.1Unpublished
2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthaseMECSAF250236.1[22]
1-hydroxy-2-methyl-2-butenyl 4-diphosphate synthaseHDSJN217103.1[23]
1-hydroxy-2-methyl-2-butenyl 4-diphosphate reductaseHDRDQ848676.1Unpublished
Cytochrome P450 reductaseCPRX69791.1[24]
Geraniol synthaseGESJN882024.1[25]
Geraniol 10-hydroxylaseG10HAJ251269.1[26]
10-hydroxygeraniol oxidoreductase10-HGOAY352047.1Unpublished
Iridoid synthaseIRSJX974564.1[27]
7-deoxyloganetic acid synthase7DLS[28]
7-deoxyloganetic acid glucosyltransferaseDLGTAB733667.1[29]
7-deoxyloganic acid 7-hydroxylaseDL7HKF415115.1[30]
Loganic acid O-methyltransferaseLAMTEU057974.1[31]
Secologanin synthaseSLSL10081.1[32,33]
Anthranilate synthaseα subunitASαAJ250008.1Unpublished
Tryptophan decarboxylaseTDC[34]
Strictosidine synthaseSTRX53602.1[35]
Strictosidine β-d-glucosidaseSGDAF112888.1[36]
Tabersonine 16- hydroxylaseT16HFJ647194.1[37]
16-hydroxytabersonine O-methyltransferase16OMTEF444544.1[38]
deacetylvindoline 4-O-acetyltransferaseDATAF053307.1[39]
Peroxidase 1PRX1AM236087.1[40]
Tab.1  Molecular characterization of enzymes involved in the biosynthetic pathway of TIAs in C. roseus
Fig.4  The biosynthesis of catharanthine and vindoline. Abbreviations: STR: strictosidine synthase; SGD: strictosidine β-D-glucosidase. Dashed arrows indicate uncharacterized steps.
Fig.5  The biosynthesis of vinblastine and vincristine. Abbreviations: T16H: tabersonine 16-hydroxylase; OMT: O-methyltransferase; NMT: N-methyltransferase; D4H: desacetoxyvindoline 4-hydroxylase; DAT: deacetylvindoline-4-O-acetyltransferase; PRX1: peroxidase 1. Dashed arrows indicate uncharacterized steps.
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