Sparteine

Sparteine

Sparteine

Chemical compound

Sparteine is a class 1a antiarrhythmic agent and sodium channel blocker. It is an alkaloid and can be extracted from scotch broom. It is the predominant alkaloid in Lupinus mutabilis, and is thought to chelate the bivalent metals calcium and magnesium. It is not FDA approved for human use as an antiarrhythmic agent, and it is not included in the Vaughan Williams classification of antiarrhythmic drugs.

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It is also used as a chiral ligand in organic chemistry, especially in syntheses involving organolithium reagents.

Biosynthesis

Originally proposed biosynthesis pathway of sparteine

Sparteine is a lupin alkaloid containing a tetracyclic bis-quinolizidine ring system derived from three C5 chains of lysine, or more specifically, L-lysine.[1] The first intermediate in the biosynthesis is cadaverine, the decarboxylation product of lysine catalyzed by the enzyme lysine decarboxylase (LDC).[2] Three units of cadaverine are used to form the quinolizidine skeleton. The mechanism of formation has been studied enzymatically, as well as with tracer experiments, but the exact route of synthesis still remains unclear.

Tracer studies using 13C-15N-doubly labeled cadaverine have shown three units of cadaverine are incorporated into sparteine and two of the C-N bonds from two of the cadaverine units remain intact.[3] The observations have also been confirmed using 2H NMR labeling experiments.[4]

Enzymatic evidence then showed that the three molecules of cadaverine are transformed to the quinolizidine ring via enzyme bound intermediates, without the generation of any free intermediates. Originally, it was thought that conversion of cadaverine to the corresponding aldehyde, 5-aminopentanal, was catalyzed by the enzyme diamine oxidase.[5] The aldehyde then spontaneously converts to the corresponding Schiff base, Δ1-piperideine. Coupling of two molecules occurs between the two tautomers of Δ1-piperideine in an aldol-type reaction. The imine is then hydrolyzed to the corresponding aldehyde/amine. The primary amine is then oxidized to an aldehyde followed by formation of the imine to yield the quinolizidine ring.[5]

Via 17-oxosparteine synthase

More recent enzymatic evidence has indicated the presence of 17-oxosparteine synthase (OS), a transaminase enzyme.[6][7][8][9][10][11] The deaminated cadaverine is not released from the enzyme, thus is can be assumed that the enzyme catalyzes the formation of the quinolizidine skeleton in a channeled fashion .[9][10][11] 7-oxosparteine requires four units of pyruvate as the NH2 acceptors and produces four molecules of alanine. Both lysine decarboxylase and the quinolizidine skeleton-forming enzyme are localized in chloroplasts.[12]

Biosynthesis of sparteine by 17-oxosparteine synthase
Proposed ring cyclization steps
Overall schematic

See also

References

  1. [1]
    Dewick PM (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). Wiley. pp. 328–329. doi:10.1002/9780470742761. ISBN 978-0-470-74276-1.
  2. [2]
    Golebiewski WM, Spenser ID (1988). "Biosynthesis of the lupine alkaloids. II. Sparteine and lupanine". Canadian Journal of Chemistry. 66 (7): 1734–1748. doi:10.1139/v88-280.
  3. [3]
    Rana J, Robins DJ (1983). "Quinolizidine alkaloid biosynthesis: Incorporation of [1-amino-15N,1-13C]cadaverine into sparteine". Journal of the Chemical Society, Chemical Communications. 1983 (22): 1335–1336. doi:10.1039/C39830001335.
  4. [4]
    Fraser AM, Robins DJ (1984). "Incorporation of chiral [1-2H]cadaverines into the quinolizidine alkaloids sparteine, lupanine, and angustifoline". Journal of the Chemical Society, Chemical Communications. 1984 (22): 1477–1479. doi:10.1039/C39840001477.
  5. [5]
    Aniszewski T (2007). Alkaloids – Secrets of Life: Alkaloid Chemistry, Biological Significance, Applications and Ecological Role. Elsevier. pp. 98–101. doi:10.1016/B978-0-444-52736-3.X5000-4. ISBN 978-0-444-52736-3.
  6. [6]
    Wink M, Hartmann T (1985). "Enzymology of quinolizidine alkaloid biosynthesis". In Zalewski RI, Skolik JJ (eds.). Natural Products Chemistry 1984: A Collection of Invited Section and Colloquium Lectures Presented at the 14th IUPAC International Symposium on the Chemistry of Natural Products, Poznań, Poland, 9–14 July 1984. Studies in Organic Chemistry. Vol. 20. Elsevier. pp. 511–520. ISBN 978-0-444-42457-0.
  7. [7]
    Wink M (1987). "Quinolizidine alkaloids: Biochemistry, metabolism, and function in plants and cell suspension cultures". Planta Medica. 53 (6): 509–514. doi:10.1055/s-2006-962797. PMID 17269092.
  8. [8]
    Wink M, Hartmann T (1979). "Cadaverine–pyruvate transamination: The principal step of enzymatic quinolizidine alkaloid biosynthesis in Lupinus polyphyllus cell suspension cultures". FEBS Letters. 101 (2): 343–346. doi:10.1016/0014-5793(79)81040-6. PMID 446758.
  9. [9]
    Perrey R, Wink M (1988). "On the role of Δ1-piperideine and tripiperideine in the biosynthesis of quinolizidine alkaloids". Zeitschrift für Naturforschung. 43c (5–6): 363–369. doi:10.1515/znc-1988-5-607.
  10. [10]
    Saito K, Murakoshi I (1995). "Chemistry, biochemistry and chemotaxonomy of lupine alkaloids in the Leguminosae". In Atta-ur-Rahman (ed.). Structure and Chemistry (Part C). Studies in Natural Products Chemistry. Vol. 15. Elsevier. p. 537. doi:10.1016/S1572-5995(06)80142-0. ISBN 978-0-444-82083-9.
  11. [11]
    Roberts MF (1998). "Enzymology of alkaloid biosynthesis". In Roberts MF, Wink M (eds.). Alkaloids: Biochemistry, Ecology, and Medicinal Applications. Plenum Press. pp. 112–114. doi:10.1007/978-1-4757-2905-4_5. ISBN 978-1-4757-2905-4.
  12. [12]
    Wink M, Hartmann T (1980). "Enzymatic synthesis of quinolizidine alkaloids in lupin chloroplasts". Zeitschrift für Naturforschung. 35c (1–2): 93–97. doi:10.1515/znc-1980-1-218.
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