Plant Natural Products (Terpenoid) Biosynthesis Enzyme Mechanisms and Engineering
Biochemical Pathway Identification (Functional Genomics)
4216 Molecular Biology Building
Dept. of Biochemistry, Biophysics & Molecular Biology
Iowa State University
Ames, IA 50011
Phone: (515) 294-8580
B.S., Molecular Biology, UC San Diego, 1992
Ph.D., Biochemistry, UC San Francisco, 1998
Postdoctoral Fellow, Washington State University, 1998-2002
Research in the Peters laboratory is focused on the large class of diterpenoid natural products, largely those falling within the labdane-related superfamily. Bioactivity of these ~7,000 known compounds ranges from the gibberellic acid (GA) hormones ubiquitously found in higher/flowering plants to natural antibiotics, and includes compounds of pharmaceutical and industrial relevance. Their biosynthesis is unified in being initiated by a pair of terpene synthase catalyzed reactions. Beginning with a poorly understood acid/base catalyzed (class II) cyclization reaction, which forms the bicyclic core that defines this super-family of compounds, and proceeding through a more typical allylic diphosphate ionization driven (class I) reaction. The resulting cyclic hydrocarbon is generally then oxygenated via the action of cytochromes P450, with the ensuing compounds often further elaborated by redox reactions and/or addition of various chemical groups by transferases.
The importance of GA for plant growth and development resulted in early investigations of their biosynthesis including identification of all the enzymes involved in GA metabolism from plants, as well as from the phytopathogenic fungus Gibberella fujikuroi, from which GA was first isolated. We are engaged in mechanistic studies of the relevant enzymes from the model plant species Arabidopsis thaliana. This provides deeper insights into this critical metabolic pathway, e.g. for identification of potential biochemical regulatory mechanisms, and also provides a baseline against which the specificity of enzymes involved in alternative biosynthetic pathways can be measured. In addition, we have begun investigating the production of GA by certain (rhizo)bacteria as well.
The absolute requirement for GA phytohormones in all flowering plants provides a reservoir of biosynthetic genes, duplication of which (e.g., as a result of the whole genome duplications that are prevalent in plant evolutionary history as well as gene duplication events) has enabled the derivation of alternative diterpenoid metabolism. For example, rice (Oryza sativa) produces more than twenty labdane-related diterpenoid natural products, many of which act as natural antibiotics against the devastating fungal blast pathogene Magneporthe oryzae. Underlying this rice phytochemical diversity is a correspondingly complex metabolic network, and we are taking a functional genomics based approach to elucidate the enzymatic activity of potential diterpenoid biosynthetic genes from this model cereal crop plant. Moreover, our identification of the relevant enzymatic genes enables a reverse genetic approach to investigation of the biological relevance/activity of the rice diterpenoids.
Finally, among the many labdane-related diterpenoid natural products are a number of compounds with significant potential to impact human health, ranging from potential and realized pharmaceuticals to a virulence factor in the human pathogen Mycobacterium tuberculosis. Accordingly, we are studying the biosynthesis of these natural products as well, which is expected to both provide increased access to this large superfamily, through enzymatic and metabolic engineering efforts, along with elucidating mechanistic features of potential drug targets against M. tuberculosis.
1: Mann FM, Peters RJ. Isotuberculosinol: the unusual case of an immunomodulatory
diterpenoid from Mycobacterium tuberculosis.. Medchemcomm. 2012 Aug
1;3(8):899-904. PubMed PMID: 23926455; PubMed Central PMCID: PMC3733278.
2: Guo J, Zhou YJ, Hillwig ML, Shen Y, Yang L, Wang Y, Zhang X, Liu W, Peters RJ,
Chen X, Zhao ZK, Huang L. CYP76AH1 catalyzes turnover of miltiradiene in
tanshinones biosynthesis and enables heterologous production of ferruginol in
yeasts. Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):12108-13. doi:
10.1073/pnas.1218061110. Epub 2013 Jun 28. PubMed PMID: 23812755; PubMed Central
3: Wu Y, Wang Q, Hillwig ML, Peters RJ. Picking sides: Distinct roles for CYP76M6
and -8 in rice oryzalexin biosynthesis. Biochem J. 2013 Jun 25. [Epub ahead of
print] PubMed PMID: 23795884.
4: Kato-Noguchi H, Peters RJ. The role of momilactones in rice allelopathy. J
Chem Ecol. 2013 Feb;39(2):175-85. doi: 10.1007/s10886-013-0236-9. Epub 2013 Feb
6. PubMed PMID: 23385366.
5: Criswell J, Potter K, Shephard F, Beale MH, Peters RJ. A single residue change
leads to a hydroxylated product from the class II diterpene cyclization catalyzed
by abietadiene synthase. Org Lett. 2012 Dec 7;14(23):5828-31. doi:
10.1021/ol3026022. Epub 2012 Nov 20. PubMed PMID: 23167845; PubMed Central PMCID:
6: Mann FM, Xu M, Davenport EK, Peters RJ. Functional characterization and
evolution of the isotuberculosinol operon in Mycobacterium tuberculosis and
related Mycobacteria. Front Microbiol. 2012 Oct 12;3:368. doi:
10.3389/fmicb.2012.00368. PubMed PMID: 23091471; PubMed Central PMCID:
7: Zhou K, Xu M, Tiernan M, Xie Q, Toyomasu T, Sugawara C, Oku M, Usui M,
Mitsuhashi W, Chono M, Chandler PM, Peters RJ. Functional characterization of
wheat ent-kaurene(-like) synthases indicates continuing evolution of
labdane-related diterpenoid metabolism in the cereals. Phytochemistry. 2012
Dec;84:47-55. doi: 10.1016/j.phytochem.2012.08.021. Epub 2012 Sep 22. PubMed
PMID: 23009879; PubMed Central PMCID: PMC3483413.
8: Wu Y, Zhou K, Toyomasu T, Sugawara C, Oku M, Abe S, Usui M, Mitsuhashi W,
Chono M, Chandler PM, Peters RJ. Functional characterization of wheat copalyl
diphosphate synthases sheds light on the early evolution of labdane-related
diterpenoid metabolism in the cereals. Phytochemistry. 2012 Dec;84:40-6. doi:
10.1016/j.phytochem.2012.08.022. Epub 2012 Sep 23. PubMed PMID: 23009878; PubMed
Central PMCID: PMC3483432.
9: Gao Y, Honzatko RB, Peters RJ. Terpenoid synthase structures: a so far
incomplete view of complex catalysis. Nat Prod Rep. 2012 Oct;29(10):1153-75. doi:
10.1039/c2np20059g. Epub 2012 Aug 21. Review. PubMed PMID: 22907771; PubMed
Central PMCID: PMC3448952.
10: Zu L, Xu M, Lodewyk MW, Cane DE, Peters RJ, Tantillo DJ. Effect of
isotopically sensitive branching on product distribution for pentalenene
synthase: support for a mechanism predicted by quantum chemistry. J Am Chem Soc.
2012 Jul 18;134(28):11369-71. doi: 10.1021/ja3043245. Epub 2012 Jul 9. PubMed
PMID: 22738258; PubMed Central PMCID: PMC3402234.
11: Wang Q, Hillwig ML, Wu Y, Peters RJ. CYP701A8: a rice ent-kaurene oxidase
paralog diverted to more specialized diterpenoid metabolism. Plant Physiol. 2012
Mar;158(3):1418-25. doi: 10.1104/pp.111.187518. Epub 2012 Jan 12. PubMed PMID:
22247270; PubMed Central PMCID: PMC3291257.
12: Zhou K, Gao Y, Hoy JA, Mann FM, Honzatko RB, Peters RJ. Insights into
diterpene cyclization from structure of bifunctional abietadiene synthase from
Abies grandis. J Biol Chem. 2012 Feb 24;287(9):6840-50. doi:
10.1074/jbc.M111.337592. Epub 2012 Jan 4. PubMed PMID: 22219188; PubMed Central
13: Wang Q, Hillwig ML, Okada K, Yamazaki K, Wu Y, Swaminathan S, Yamane H,
Peters RJ. Characterization of CYP76M5-8 indicates metabolic plasticity within a
plant biosynthetic gene cluster. J Biol Chem. 2012 Feb 24;287(9):6159-68. doi:
10.1074/jbc.M111.305599. Epub 2012 Jan 3. PubMed PMID: 22215681; PubMed Central
14: Xu M, Galhano R, Wiemann P, Bueno E, Tiernan M, Wu W, Chung IM, Gershenzon J,
Tudzynski B, Sesma A, Peters RJ. Genetic evidence for natural product-mediated
plant-plant allelopathy in rice (Oryza sativa). New Phytol. 2012
Feb;193(3):570-5. doi: 10.1111/j.1469-8137.2011.04005.x. Epub 2011 Dec 12. PubMed
PMID: 22150231; PubMed Central PMCID: PMC3257406.
15: Hillwig ML, Xu M, Toyomasu T, Tiernan MS, Wei G, Cui G, Huang L, Peters RJ.
Domain loss has independently occurred multiple times in plant terpene synthase
evolution. Plant J. 2011 Dec;68(6):1051-60. doi:
10.1111/j.1365-313X.2011.04756.x. Epub 2011 Oct 17. PubMed PMID: 21999670; PubMed
Central PMCID: PMC3237789.
16: Wu Y, Hillwig ML, Wang Q, Peters RJ. Parsing a multifunctional biosynthetic
gene cluster from rice: Biochemical characterization of CYP71Z6 & 7. FEBS Lett.
2011 Nov 4;585(21):3446-51. doi: 10.1016/j.febslet.2011.09.038. Epub 2011 Oct 5.
PubMed PMID: 21985968; PubMed Central PMCID: PMC3227696.
17: Mafu S, Hillwig ML, Peters RJ. A novel labda-7,13e-dien-15-ol-producing
bifunctional diterpene synthase from Selaginella moellendorffii. Chembiochem.
2011 Sep 5;12(13):1984-7. doi: 10.1002/cbic.201100336. Epub 2011 Jul 12. PubMed
PMID: 21751328; PubMed Central PMCID: PMC3383829.
18: Köksal M, Hu H, Coates RM, Peters RJ, Christianson DW. Structure and
mechanism of the diterpene cyclase ent-copalyl diphosphate synthase. Nat Chem
Biol. 2011 May 22;7(7):431-3. doi: 10.1038/nchembio.578. PubMed PMID: 21602811;
PubMed Central PMCID: PMC3118866.
19: Morrone D, Hillwig ML, Mead ME, Lowry L, Fulton DB, Peters RJ. Evident and
latent plasticity across the rice diterpene synthase family with potential
implications for the evolution of diterpenoid metabolism in the cereals. Biochem
J. 2011 May 1;435(3):589-95. doi: 10.1042/BJ20101429. PubMed PMID: 21323642;
PubMed Central PMCID: PMC3723722.
20: Zhou K, Peters RJ. Electrostatic effects on (di)terpene synthase product
outcome. Chem Commun (Camb). 2011 Apr 14;47(14):4074-80. doi: 10.1039/c0cc02960b.
Epub 2011 Feb 8. PubMed PMID: 21305070; PubMed Central PMCID: PMC3718459.