crgoldsm@stanford.edu Graduate Student      Born in 1975. USA. Education: Harvard University (Cambridge, MA); A.B. in  Chemistry, 1998. R. H. Holm, advisor.

Interests in the StackLab: Lipoxygenase Models

Lipoxygenases are mononuclear non-heme iron enzymes that catalyze the oxidation of 1,4-pentadiene containing fatty acids to alkyl hydroperoxides. The hydroperoxide products are precursors to a number of physiological effectors such as leukotrienes and lipoxins, and lipoxygenase activity has been linked to a number of inflammatory conditions as well as angiogenesis in certain forms of cancer. Lipoxygenase oxidation is generally believed to occur through an initial hydrogen atom abstraction from the 3-position of the 1,4-pentadiene subunit by an Fe(III)-hydroxide species to form an organic radical and an Fe(II)-water species. The organic radical rearranges before molecular oxygen is regio- and stereospecifically incorporated into the molecule. The resultant alkyl peroxide radical then abstracts a hydrogen atom from the Fe(II)-water species to regenerate the Fe(III)-hydroxide form of the enzyme. Our lab has developed a small molecule mimic of the active form of the enzyme. Using the pentadentate ligand PY5 to model the histidine-heavy coordination sphere of lipoxygenase, we made the complex [Fe(III)(PY5)(OMe)]2+, which is capable of cleaving weak (< 90 kcal/mol) C-H bonds. Primary kinetic isotope effects are observed with deuterated substrates, and the reactivity scales with the bond dissociation energy of the C-H bond. Both of these observations are consistent with a hydrogen atom abstraction as the rate-determining step in the mechanism. Currently, efforts to generate a second generation of lipoxygenase mimics are underway.
 

Publications: (click on the number to get the pdf file)

(7) Hydrogen Atom Abstraction by a Mononuclear Ferric Hydroxide Complex: Insights into the Reactivity of Lipoxygenase
Goldsmith, C. R.; Stack, T. D. P.
Inorg. Chem.2006, ASAP.

(6) C-H Activation by a Mononuclear Manganese(III) Hydroxide Complex: Synthesis and Characterization of a Manganese-Lipoxygenase Mimic?
Goldsmith C.R., Cole A.P., Stack T.D.P.
J. Am. Chem. Soc. 2005, 127. 27, 9904-9912.

(5) X-ray Absorption Spectroscopic Investigation of the Spin-Transition Character in a Series of Single-Site Perturbed Iron(II) Complexes
Jackson Rudd D., Goldsmith C.R., Cole A.P., Stack T.D.P., Hodgson K.O., Hedman B.
Inorg. Chem. 2005, 44, 5, 1221-1229.

(4) A Spectrochemical Walk: Single-Site Perturbation within a Series of Six-Coordinate Ferrous Complexes
Goldsmith C.R., Jonas R.T., Cole A.P., Stack T.D.P.
Inorg. Chem. 2002, 41, 18, 4642-4652.

(3) A Periodic Walk: A Series of First-Row Transition Metal Complexes with the Pentadentate Ligand PY5
Klein-Gebbink R.J.M., Jonas R.T., Goldsmith C.R., Stack T.D.P.
Inorg. Chem. 2002, 41, 18, 4633-4641.

(2) C-H bond activation by a ferric methoxide complex: Modeling the rate-determining step in the mechanism of lipoxygenase
Goldsmith C.R., Jonas R.T., Stack T.D.P.
J. Am. Chem. Soc. 2002, 124, 1, 83-96.

(1) Synthesis, structures, and reactivity of bis(dithiolene)molybdenum(IV,VI) complexes related to the active sites of molybdoenzymes
Donahue J.P., Goldsmith C.R., Nadiminti U., Holm R.H.
J. Am. Chem. Soc. 1998, 120, 49, 12869-12881.