MPS Advanced Plant Biochemistry Course. Fall Semester Lecture 22. Alkaloids IV

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1 MPS Advanced Plant Biochemistry Course Fall Semester 2011 Lecture 22 Alkaloids IV 14. Alkaloids derived from strictosidine 14a. Indole alkaloids 14b. Quinoline alkaloids

2 Disclaimer As part of the alkaloid biosynthesis section of this lecture, I will cover various illicit uses and share some stories of people who have used extracts and preparations containing mind-altering alkaloids. Herewith I would like to state very clearly that this is not meant to play down the dangers associated with the illicit use of drugs, nor do I support in any way the use of such materials. B.M. Lange (Course director) 2

3 Alkaloids derived from strictosidine 3

4 Precursor biosynthesis secologanin is derived from the MEP pathway (O Connor & Maresh (2006) Natural Product Reports 23, 532) 4

5 Precursor biosynthesis strictosidine is formed by a condensation of tryptamine and secologanin (O Connor & Maresh (2006) Natural Product Reports 23, 532) 5

6 Structure and mechanism of strictosidine synthase (Stöckigt et al. (2008) Plant Physiology and Biochemistry 46, 340) (B) Structure of STR1- tryptamine-complex. The active site is located near the pseudo-six-fold symmetry axis. (C) Side view of STR1 in complex with secologanin. Reaction mechanism of STR1-catalyzed Pictet Spengler condensation. (A) Side view of STR1 in complex with tryptamine and aligned with secologanin and close-up view of the active site. Glu309 is highlighted as a stick representation. (B) The reaction mechanism as it occurs in the substrate binding pocket of STR1, leading to 3-α-(S )-strictosidine. (C) Crystal structure of STR1-strictosidine complex, close-up view of the catalytic residue Glu309 and the STR1 product strictosidine. 6

7 Strictosidine-derived alkaloids of Rauvolfia serpentina 7

8 Ajmaline (O Connor & Maresh (2006) Natural Product Reports 23, 532) Found in the root of Rauvolfia serpentina, among other plant sources. It is a class Ia antiarrhythmic agent that apparently acts by changing the shape and threshold of cardiac action potentials. 8

9 Vinorine synthase is a member of the BAHD superfamily of acetyltransferases (Ma et al. (2006) Journal of Biological Chemistry 280, 13576) Ribbon diagram of VS with modeled CoA (in black). There are 19 residues that are strictly conserved and belong exclusively to domain 1. These residues are indicated with black balls at the Cα positions and labeled with the respective residue name. 9

10 Strictosidine-derived alkaloids of Catharanthus roseus Source: Wikipedia 10

11 Vinblastine and vincristine (Bisindole type) Source: Wikipedia Vinblastine is a vinca alkaloid and a chemical analogue of vincristine. It binds tubulin, thereby inhibiting the assembly of microtubules. It is G1-S phase cell cycle specific. Vinblastine is a component of a number of chemotherapy regimens, including ABVD for Hodgkin s lymphoma. It is also used to treat histiocytosis. Vincristine binds to tubulin dimers causing disassembly of microtubule structures. Disruption of the microtubules arrests mitosis in metaphase. The vinca alkaloids therefore affect all rapidly dividing cell types, including cancer cells but also as intestinal epithelium and bone marrow. Main uses are in non Hodgkin's lymphoma as part of the chemotherapy regimen CHOP, Hodgkin's lymphoma as part of the Stanford V chemotherapy regimen, and in acute lymphoblastic leukemia. The market price for vinblastine and vincristine extracted from the plant is estimated at $2 million/kg and $15 million/kg, respectively. 11

12 Overview of Vinca alkaloid biosynthesis Color coding: Cytosol, yellow; ER membrane, purple; Vacuole, pink; Plastid, green. 12

13 Trafficking in indole alkaloid metabolism (Ziegler & Facchini (2008) Annual Reviews in Plant Biology 59, 735) IPAP = internal phloemassociated parenchyma 13

14 Strictosidine-derived quinoline alkaloids of cinchona bark Source: Wikipedia 14

15 Mutasynthesis of unnatural alkaloids in cell cultures (Leonard et al. (2009) Nature Chemical Biology 5, 292) 15

16 Properties of quinine Quinine is present is the bark of various trees of the genus Cinchona (family Rubiaceae), which are native to tropical South America. Antipyretic, anti-malarial with analgesic and anti-inflammatory properties Followed by synthetic analogue chloroquine Now again the drug of choice for treatment of Plasmodium falciparum malaria because of the rise of chloroquine resistance. Interferes with the parasite's ability to break down and digest hemoglobin, thus starving the parasite and/or causing the build-up of toxic levels of partially degraded hemoglobin in the parasite. Non-medical use in popular drinks such as tonic water and bitter lemon. 16

17 Proposed pathway for the biosynthesis of quinine (O Connor & Maresh (2006) Natural Product Reports 23, 532) 17

18 Strictosidine-derived alkaloids of Camptotheca acuminata (Quinoline type) (Lorence & Nessler (2004) Phytochemistry 65, 2735) 18

19 Camptothecin biosynthesis (O Connor & Maresh (2006) Natural Product Reports 23, 532) Camptothecin has been identified in phylogenetically unrelated plant species. It has antitumor activity. It is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1). Eventually, this process inhibits DNA replication and transcription. Topotecan (Hycamtin ) is a chemotherapy drug that is given as a treatment for some types of cancer. It is mainly used to treat ovarian cancer or small-cell lung cancer (SCLC). Irinotecan (Campto ) is most commonly used to treat bowel cancer. The combined sales of topotecan and irinotecan exceed $ 1 billion per year. 19

20 L-Asp L-Orn NAD Putrescine Homospermidine L-Ile Nicotinic acid N-Methylputrescine Pyrrolizidine alkaloids Nicotine Ψ-Tropine Tropinone Tropine AcAc-CoA Tropic acid L-Phe 4-Hydroxyphenylacetaldehyde L-Tyr Dopamine Calystegines Tropane alkaloids Phenylethylamine alkaloids (S)-Reticuline Benzylisoquinoline alkaloids L-Trp GAP + Pyruvate Ac-CoA Tryptamine Secologanin MVA Indole alkaloids Strictosidine Quinoline alkaloids Sterol Glycoalkaloids L-Arg Overview of alkaloid biosynthetic pathways 20