PROFILE

Profile of Edward I. Solomon hen ‘‘iron’’ comes up in school, he became involved in a pro- conversation, it is often gram set up by Dade County in Florida, thought of in dietary which allowed exceptional students to terms. Found in meats, work with university . So- beans,W and leafy vegetables, the blood lomon studied with a at the requires iron to carry oxygen throughout University of Miami (Miami, FL), using the body, such as to the muscles, via and chromatography to hemoglobin. Iron deficiencies can lead study indols. The project led to Solomon to anemia. Edward Solomon, Monroe E. becoming Florida’s first-ever finalist for Spaght Professor of at Stan- the Westinghouse (now Intel) Science ford University (Stanford, CA), has de- Talent Search in 1964. voted much of his research to studying When it came time to think about an entirely different aspect of iron, its college, Solomon recalls that one of his role in non-heme enzymes that catalyze friends from New York had frequently important biochemical reactions. ‘‘The mentioned that Rensselaer Polytechnic non-heme iron proteins are all over the Institute (RPI; Troy, NY) would be a place,’’ he says. ‘‘When you read a can great fit for Solomon’s interests. ‘‘I just of diet soda and it says, ‘Phenylketonu- connected with it, and that’s where I rics, don’t drink this,’ that’s because of a went. Although once I got there, I was non-heme iron enzyme that converts shocked because I had never seen snow phenylalanine to tyrosine, and muta- before, and it was pretty cold,’’ he says. tions, often near the active site, lead to Although adjusting to the weather took poor enzyme catalysis and ultimately the some time, what gave Solomon trouble disease, PKU.’’ Furthermore, many en- Edward I. Solomon in his first few years was organic chemis- zymes responsible for antibiotic synthe- try, so much so that he considered sis and bioremediation are also non- switching majors to psychology, which, heme iron-based. ‘‘It’s massive,’’ says copper-containing enzymes, helping an- between some elective courses and his Solomon. swer fundamental questions in that area. previous studies on schizophrenia, he For over 30 years, Solomon has stud- For example, Solomon first demon- found interesting. ‘‘But you know, I was ied metalloenzymes with a chemist’s strated the presence of a trinuclear cop- really a chemist at heart,’’ he says, ‘‘and eye, using both theoretical calculations per cluster in biology and that it plays once I went into the physical chemistry and to visualize these bio- the key role in the reduction of oxygen courses, particularly quantum chemistry, inorganic systems and to gain an under- to water (2). Today, Solomon is ready to it just took off.’’ standing of how they work. ‘‘These branch out to other metals and their Solomon remembers two professors, enzymes really reflect novel electronic complexes, and there is no shortage to Sam Wait and Henry Hollinger, who structures, highly covalent sites that acti- pick from. ‘‘You know, somewhere were influential in giving Solomon his vate an inorganic metal, and we’ve been around one-third of all enzymes require first work in theoretical chemistry. ‘‘As defining the role of the protein in tun- a metal for catalysis. It’s just amazing an undergraduate, I became really inter- ing the geometric and electronic struc- how many places metals are and what ested in some concepts in transition ture of a metal site to do its chemistry,’’ they do,’’ he says. metal ,’’ says So- he says. Because different spectroscopy lomon, ‘‘such as 10Dq, which is a split- techniques yield different information, Kitchen Chemistry ting of d orbitals in a ligand field, and Solomon has used a wide range of Solomon first discovered the wonders the Jahn–Teller effect, which is how methods, many developed by his own of science before he started school, electronic structure leads to geometry.’’ laboratory, to obtain a comprehensive while visiting relatives in New York After graduating from RPI in 1968, picture of the structural and chemical City. The trip included eye-opening vis- those interests led Solomon to pursue properties of non-heme iron enzymes. its to several museums, as well as the doctoral studies with Don McClure, a Elected to the National of Hayden Planetarium, which Solomon spectroscopist and expert on transition Sciences in 2005, Solomon presents his remembers with particular fondness. Af- metal systems who had recently moved Inaugural Article in this issue of PNAS ter his return home to North Miami to Princeton University (Princeton, NJ). (1). In the paper, he uses spectroscopic Beach, FL, Solomon began acquiring his ‘‘What I really liked about McClure is techniques to examine the relationship science ‘‘toys’’: a telescope, a micro- that he was really at the edge of theory between the two main classes of non- scope, a mineral collection, a Tasco bio- with experiment[s]. . . . I could do some heme iron enzymes: those that abstract slide kit, and a Gilbert chemistry set. ‘‘I very fundamental experiments and eval- hydrogen and those that attack bonds. sort of took off on that,’’ he says, ‘‘and I uate how well the concepts worked,’’ He finds that both classes are similar guess I didn’t look back.’’ Over the says Solomon. and go through the same reaction inter- years, the chemistry set expanded to a Unfortunately, Solomon soon found mediate. Such findings further the un- full chemistry laboratory in the garage, that theory and practice do not always derstanding of how non-heme iron displacing the Solomons’ family car. see eye to eye. ‘‘I was taking a single enzymes catalyze key biochemical trans- When Solomon was not conducting crystal of rubidium manganese fluoride, formations, many of which have biomed- homemade chemistry experiments or

ical and environmental significance. occasionally getting stitches from break- This is a Profile of a recently elected member of the National Solomon’s work has not been re- ing glass test tubes, he excelled at sci- Academy of Sciences to accompany the member’s Inaugural stricted to non-heme iron. He has also ence in school, winning numerous Article on page 12966. designed and applied spectroscopy to science fairs. In his junior year of high © 2006 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0606007103 PNAS ͉ August 29, 2006 ͉ vol. 103 ͉ no. 35 ͉ 12963–12965 Downloaded by guest on September 26, 2021 CalTech starting in 1974. When Gray first showed him a spectrum of the nickel ion in the enzyme carboxypepti- dase, Solomon saw similar patterns to what he observed in hex-aqua nickel. He realized he could apply some of the same concepts he had learned for inorganic spectroscopy toward these proteins. Solomon began studying blue copper proteins, such as plastocyanin and azurin, and based on several experi- ments, he determined the basic struc- ture of the copper active site (5). These results were confirmed a few years later when Hans Freeman at the University of Sydney (Sydney, Australia) solved the crystal structure of a blue copper pro- tein (6). Solomon continued to study blue copper proteins when he moved back to the East Coast in 1975 to join the Massachusetts Institute of Technol- ogy (MIT; Boston, MA) as an assistant professor. At MIT, he began looking at the spectroscopic features of binuclear cop- Solomon speaking to his laboratory group. per proteins that bind oxygen. He also expanded his work to two other areas: which I had spent a long time getting research group. ‘‘I had started to think (i) examining the excited states of pho- perfectly set up, and putting it in a large about being a professor, so it was a toactive transition metal complexes to piston in the middle of liquid helium, so chance to see what running a lab was understand inorganic photochemistry I could see how the spectral states like,’’ Solomon says. He also had an and (ii) investigating how small mole- would be impacted by a distortion in the idea of the research he would like to cules on metal oxide surfaces are acti- environment,’’ he explains. What he ob- pursue once he became a professor, vated for catalysis. By 1982, however, served, however, was that the more data thanks to a symposium hosted by Mc- when he joined Stanford University as a he put into his experimental model, the Clure and fellow Princeton chemist Tom professor, he enjoyed working on biolog- less the theory predicted the results. Spiro. ‘‘They had brought in everybody ical metals so much that it became the ‘‘And that got me really stressed out,’’ from the broad field of physical inor- dominant focus of his laboratory. he says, ‘‘but Princeton was a wonderful ganic chemistry, from the theoretical Non-Heme in Northern California place, where you could walk around physicists to synthetic chemists,’’ So- campus and think about things and just lomon says, ‘‘and I could really see the Solomon’s exposure to a wide variety of keep thinking.’’ So, like Albert Einstein, direction I wanted to go next, which was spectroscopic techniques at CalTech and John Nash, and others before, Solomon to look at really interesting molecules, MIT, such as novel types of magnetic wandered the ivied grounds of Prince- such as metalloenzymes. All of a sudden circular dichroism and x-ray photoelec- ton’s campus until he figured out the you have these metal sites in proteins tron spectroscopy specially designed for problem. ‘‘There was a way that the that have completely different spectro- protein analysis, established his ability analysis should have been done, in how scopic features than anything seen in to utilize different experimental meth- you input the terms in a Hamiltonian small-molecule inorganic chemistry.’’ ods as well as develop new ones. This and do the calculation, that people A leader in metalloenzyme research ability became an important component weren’t doing,’’ he says. A Hamiltonian was Harry Gray at the California Insti- of Solomon’s own laboratory and played is a mathematical function that can be tute of Technology (CalTech; Pasadena, a major role in his decision to move used to generate the equations of mo- CA), and Solomon wanted to set up from MIT to Stanford. ‘‘I wanted to tion of a dynamic system. When he went a postdoctoral position there. First, have a wide range of methods available back to his computer and tried his new however, Solomon spent a year in that we could apply rigorously to study approach, the output looked just like his Copenhagen, Denmark to work under metalloenzymes and related systems,’’ data and predicted several other things Carl Ballhausen, to better understand he says, ‘‘and having the synchrotron [at he had seen in the experiment as well both sides of the theory͞experiment Stanford] was attractive and gave me a (3). ‘‘And that was a big thing for me, in coin. ‘‘McClure was an experimentalist chance to put together a really unique terms of feeling that I was a Ph.D. type who was at the edge of theory,’’ explains spectroscopy laboratory.’’ Of course, and could really go on and solve what- Solomon, ‘‘while Ballhausen was a theore- other factors, such as the balmy Califor- ever I wanted to work on,’’ he says. tician who really focused on understand- nia weather, also helped him make his ing data.’’ Together with Ballhausen, decision to move to Stanford. ‘‘I spent Small Molecules to Big Proteins Solomon solved how some unusual po- some time out in Stanford in January Shortly after Solomon received his tential energy surfaces contributed to when I got invited to join. I’d left a Ph.D. in chemistry in 1972, his advisor the strange spectral shape of hex-aqua snowstorm in Boston and ended up eat- McClure went on sabbatical and asked nickel (4). This research served as a ing at an outdoor Mexican cafe´. That Solomon to stay and help oversee his natural segue for Solomon’s work at was pretty different,’’ he says.

12964 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0606007103 Zagorski Downloaded by guest on September 26, 2021 After he arrived at Stanford, Solomon have helped mechanistically define how worked on enzymes that used the same became interested in proteins containing certain phenylketonuria (PKU) mutants substrate, but each with a different non-heme iron, which posed an experi- affect catalysis (8). He has also worked chemistry. Using multiple spectroscopic mental difficulty. Most researchers be- with the anticancer drug bleomycin, a methods, Solomon shows that both of lieved non-heme iron was too difficult fairly large iron-containing peptide anti- these enzymes go through the same in- to study because it had no spectroscopic biotic that behaves as a pseudoenzyme termediate, ‘‘and we can see how that features. ‘‘Heme has these porphyrin and can break double-stranded DNA, intermediate should be very effective at rings,’’ explains Solomon, ‘‘and your showing how this compound activates both types of reactions,’’ he says. The blood has very intense absorption be- oxygen and subsequently cleaves study shows that the difference between cause of this porphyrin. Non-heme sites DNA (9). the classes is how the protein orients the don’t have it, so how do you see them?’’ substrate. Solomon adds that non-heme irons are In the future, Solomon would like to ferrous, and thus have an even electron “It’s great when explore how the other oxygen-activating spin, meaning that electron-spin reso- systems, such as those using copper or nance techniques also would not work we can evolve our molybdenum, relate to iron activators to study them. However, because these and to each other in their reaction cen- atoms are intense in the magnetic circu- research to deal ters. He is also interested in studying lar dichroism (MCD) spectrum, So- how metal ions in proteins interact with lomon developed a variable-temperature directly with their highly organic environment. To variable-field (VTVH) MCD method to that end, Solomon has teamed up with study these ions (7) health issues.” Keith Hodgson and Brett Hedman at Over the years, VTVH MCD has pro- the Stanford Synchrotron Radiation vided insight into the geometric and Laboratory to design new x-ray spectro- electronic structures of many non-heme In his PNAS Inaugural Article (1), scopic methods that can assess the ferrous enzymes. For Solomon, the most Solomon collaborates with Graham covalency of bonds and orbitals (10). exciting benefits of developing this new Moran and Jonathan Spencer to work Solomon plans to apply this technique method were that he could now team up on another pair of intriguing non-heme to heme to study the delocalization of with other researchers and work on iron enzymes. ‘‘There are two broad iron in the porphyrin ring. So far, at many interesting applications. ‘‘I really classes of reactions that these enzymes least, Solomon has not found a scientific love to collaborate with key researchers do. One class of enzymes does H-atom question for which he could not design who are studying different enzymes and abstraction, and the other class does an a method, but if he should ever get mutants related to a disease state or electrophilic attack on double bonds. stumped, he can always head back to such. It’s great when we can evolve our Now the question is, ‘how do they relate Princeton’s grounds for inspiration. research to deal directly with health is- to each other?’’’ says Solomon. As luck sues.’’ For instance, Solomon’s studies would have it, both Moran and Spencer Nick Zagorski, Science Writer

1. Neidig, M. L., Decker, A., Choroba, O. W., 5. Solomon, E. I., Hare, J. W. & Gray, H. B. (1976) 8. Kemsley, J. N., Wasinger, E. C., Datta, S., Mitiæ, Huang, F., Kavana, M., Moran, G. R., Spencer, Proc. Natl. Acad. Sci. USA 73, 1389–1393. N., Acharya, T., Hedman, B., Caradonna, J. P., J. B. & Solomon, E. I. (2006) Proc. Natl. Acad. Sci. 6. Colman, P. M., Freeman, H. C., Guss, J. M., Hodgson, K. O. & Solomon, E. I. (2003) J. Am. USA 103, 12966–12973. Murata, M., Norris, V. A., Ramshaw, J. A. M. Chem. Soc. 125, 5677–5686. 2. Allendorf, M. D., Spira, D. J. & Solomon, E. I. & Venkatappa, M. P. (1978) 272, 9. Decker, A., Chow, M. S., Kemsley, J. N., Lehnert, (1985) Proc. Natl. Acad. Sci. USA 82, 3063–3067. 319–324. N. & Solomon, E. I. (2006) J. Am. Chem. Soc. 128, 3. Solomon, E. I. & McClure, D. S. (1972) Phys. Rev. 7. Solomon, E. I., Brunold, T., Davis, M. I., Kemsley, 4719–4733. B 6, 1697–1708. J. N., Lee, S.-K., Lehnert, N., Nesse, F., Skulan, 10. Glaser, T., Hedman, B., Hodgson, K. O. & 4. Solomon, E. I. & Ballhausen, C. J. (1975) J. Mol. A. J., Shan, Y.-S. & Zhou, J. (2000) Chem. Rev. Solomon, E. I. (2000) Acc. Chem. Res. 33, 859– Phys. 29, 279–299. 100, 235–350. 868.

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