Trailblazers in Chemistry: From Steroids to Penicillin to Vitamin B12

1. (Chemical Crystallography Laboratory, Dept. Chemistry, University of Oxford)

2. Crystallography Group in the OCD–1954. Left to right, standing: J.H. Robertson, M. Innes, A. Chung, J. Pickworth, B. Oughton, F. Welch; seated: M. Webster, Dorothy Hodgkin, H.M. Powell, M. Mackay, D. Lawton.

3. Dorothy’s first crystallographic studies were with H. M. Powell in Oxford (thallium dialkyl halides). Bernal had shown that the chemical formula for steroids (by Wieland and Windaus) was unacceptable because the unit cell dimensions and optical properties of crystals indicate that a molecule with the given formula could not fit in the unit cell. Dorothy studied over 100 steroids and, in the days before crystal structure determinations, showed how they packed in the crystalline state. Back in Oxford she worked on the crystal structure of cholesteryl iodide with Harry Carlisle. They confirmed that the formula that Bernal suggested was correct.

4. 1932 Steroid structure (Bernal) Wieland and Windaus formulae Wieland, Dane formula (also crystal structure) Bernal, Rosenheim King formula

5. Cholesterol Cholesteryl iodide and cholesterol

6. Penicillin The serendipitous discovery of penicillin is usually attributed to Scottish scientist Alexander Fleming at St. Mary Hospital in London in 1929, though others had earlier noted the antibacterial effects of Penicillium. Fleming noticed a halo of inhibition of bacterial growth around a contaminant blue-green mould on a Staphylococcus plate culture and concluded that the mould was releasing a substance that was inhibiting bacterial growth. He named this substance "penicillin" after the Penicillium notatum mould that released it. Fleming worried about the short lifetime of penicillin in the body and therefore did not view it as a possible medication for infection. Penicillin was isolated by Howard Florey and Ernst Chain in Oxford in 1939.

7. Penicillin Penicillin kills bacterial cells when they try to divide. It works by binding to the enzyme transpeptidase that links the peptidoglycan molecules in bacteria. This weakens their cell walls. During World War II, penicillin reduced the number of infected wounds amongst the soldiers. Availability was severely limited, however, by the difficulty in manufacturing large quantities and by its rapid renal clearance necessitating frequent dosing. Most of a penicillin dose is cleared within a few hours of administration.

8. Penicillin Crystal Structure Dorothy worked on penicillin with Charles William Bunn, Barbara Rogers-Low and Annette Turner-Jones. They did X-ray analyses of Na, K and Rb benzylpenicillin and showed that the molecule has a beta-lactam structure Sir Robert Robinson did not like the beta-lactam structure because this would be unstable, unlike penicillin. J. W. Cornforth said “If penicillin turns out to have the beta-lactam structure I shall give up chemistry and grow mushrooms.” He did not keep his threat but later received a Nobel prize for his enzyme work.

9. 1949 Penicillin chemical formula b-lactam oxazolone

10. Vitamin B12 B12 deficiency is the cause of pernicious anemia. William Murphy discovered that ingesting large amounts of liver seemed to cure the disease. George Minot and George Whipple then set out to isolate the curative substance and ultimately were able to isolate vitamin B12 from liver. For this, all three shared the 1934 Nobel Prize in Medicine. The chemical structure of the molecule was determined by Dorothy Crowfoot Hodgkin and her team in 1954, based on X-ray crystallographic data.

11. Vitamin B12 can only be made by bacteria or archaea. Its structure contains a corrin ring, similar to the porphyrin ring but with two of the pyrrole rings directly bonded. The central metal ion is Co is surrounded by four pyrrole rings, and a dimethylbenzimidazole group. The sixth coordination partner varies, being CN, OH, or CH3 in Me B12 or a 5′-deoxyadenosyl group in Ado B12 (here the C5′ atom of deoxyribose forms a Co-C covalent bond to Co, the first carbon-metal ion bond found in biology). • In humans there are two coenzyme B12-dependent enzymes: • MUT (methylmalonyl-CoA mutase) uses Ado B12 and converts L-methylmalonyl-CoA to succinyl CoA, a carbon skeleton rearrangement. • MTR (methionine synthase), a methyl transfer enzyme, uses Me B12 and converts homocysteine to methionine.

12. Ada, countess of Lovelace, 1815-1852, daughter of Lord Byron the poet English mathematician known for her description of Charles Babbage’s mechanical general-purpose computer, the Analytical Engine. In her notes she introduced the first algorithm intended to be used by a machine and so she has been called the first computer programmer.

13. Patterson projections P 212121 Heavy-atom vectors P(uv) Atoms at: x,y,z 1/2-x,-y, 1/2+z 1/2+x,1/2-y,-z -x,1/2+y,1/2-z Vectors at: 0,0,0, 1/2-2x,-2y,1/2 1/2,1/2-2y,-2z -2x,1/2,1/2-2z P(uw)

14. Finding atoms in the hexaacid

15. B12 hexacarboxylic acid CN Cl

16. Vitamin B12 P

17. Vitamin B12coenzyme structure Hodgkin et al., Nature 176, 325 (1955)