Natural product’s carbon-cobalt bond surprised, inspired
In the early-20th century, doctors prescribed a diet of beef liver for those suffering from pernicious anemia. But they had only a limited understanding of why the stuff cured the otherwise deadly disease. The key turned out to be vitamin B-12, which E. Lester Smith’s group at Glaxo and another team at Merck isolated independently in 1948. Chemists immediately wanted to determine its chemical formula and structure.
So Smith sent crystals of the vitamin to University of Oxford chemist Dorothy Crowfoot Hodgkin, a pioneering crystallographer who had solved the structure of penicillin. She and her research team immediately began analyzing the ruby-red crystals.
With approximately 100 nonhydrogen atoms, vitamin B-12 was the most complex molecule yet tackled by crystallographers. Hodgkin was excited to find that it contained a cobalt atom. She had used the presence or substitution of heavy atoms to help define earlier structures, and she realized cobalt could play a similar role. She collaborated with Princeton University chemist John G. White and his team to solve the structure over about six years.
Jenny P. Glusker, now an emeritus professor at Fox Chase Cancer Center, was a graduate student in Hodgkin’s lab at the time. She remembers collecting and estimating the intensities of the diffraction data by eye and finding the position of the cobalt atom. “Each electron density map took six weeks, day and night, with a whole roomful of IBM cards,” she says. The team built a three-dimensional model with wire for bonds and wax balls for atoms—which often melted during hot summers, Glusker recalls. Kenneth N. Trueblood at UCLA helped accelerate their efforts by doing calculations with an early supercomputer.
The complete structure, published in 1956, was surprising and complex (Nature, DOI: 10.1038/178064a0). The cobalt at the center of the molecule was part of a ring structure similar to porphyrin, called the corrin ring. In 1961, Hodgkin and P. Galen Lenhert published the structure of the vitamin’s coenzyme form (Nature, DOI: 10.1038/192937a0). This was the first time biochemists had seen a carbon-cobalt bond, paving the way for advances at the interface of inorganic and biological chemistry.
At the time, some scientists minimized the sophistication required to solve B-12’s structure, Glusker says. “They thought a crystallographer was just a technician who pressed a button, and out came the answer.”
The work led to the total synthesis of vitamin B-12 by Harvard University chemist Robert Burns Woodward, Albert Eschenmoser of ETH Zurich, and collaborators in 1972. Doctors can now give shots of the vitamin to patients with pernicious anemia. In 1964 Hodgkin won the Nobel Prize in Chemistry for determining this structure and others, including penicillin. She went on to solve the structure of insulin.—Deirdre Lockwood