User:Lisa M. Leone/Sandbox 1

From Proteopedia

This is my sandbox

Add to Taxol discussion - stabilization of tubulin sheet by taxol: PDB ref IJFF : http://www.pdb.org/pdb/explore/explore.do?structureId=1JFF

Taxol Biosynthesis

Taxol is a complex diterpenoid produced mainly in the bark of the yew tree, genus Taxus. Taxol is synthesized in planta as a secondary metabolite. Secondary metabolites are produced in small quantities and are thought to provide an evolutionary benefit for plants in terms of protection against insects and disease. In cell suspension cultures, Taxol is produced in very small quantities basally, but when an elicitor is added to the media Taxol production rises dramatically. A common elicitor is methyl jasmonate (MJ), a plant hormone known to activate plant defense pathways in many species. Among other things, MJ activates a cascade resulting in expression of taxol biosynthesis proteins and re-routing of primary metabolism into secondary metabolism.

Taxol Carbon Skeleton

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The first dedicated step of the Taxol biosynthetic pathway is the conversion of geranylgeranyl diphosphate (GGPP), the precursor for all plant diterpenoids, into taxa-4,11-diene. The enzyme catalyzing the conversion of GGPP is , a lyase enzyme. TXS's crystal structure has recently been published. TXS's relies on Mg2+ metal chemistry to catalyze the reaction. (citation: Mustafa Köksal, Yinghua Jin, Robert M. Coates, Rodney Croteau & David W. Christianson Nature 469, 116–120 (06 January 2011) doi:10.1038/nature09628)

The Taxol biosynthetic pathway comprises approximately 20 steps in total, of which a few remain unknown. Efforts are currently underway in the Roberts, Walker and Normanly labs to identify the enzyme catalyzing the formation of the oxetane ring moiety in Taxol, which has been shown to be essential for its microtubule binding activity (citation: Expositio taxol paper).

Taxol side-chain

A modified phenylalanine side chain is added to the Taxol carbon skeleton (Baccatin III) late in the pathway. The first dedicated step of this side-chain pathway is the isomerization of phenylalanine, catalyzed by . PAM's crystal structure has also recently been published. PAM's relies on a 4-methylidene-1H-imidazol-5(4H)-one prosthesis characteristic of the class I lyase family. citation: Mechanistic, Mutational, and Structural Evaluation of a Taxus Phenylalanine Aminomutase Lei Feng, Udayanga Wanninayake, Susan Strom, James Geiger, and Kevin D. Walker Biochemistry 2011 50 (14), 2919-2930