- Ribonucleotide reductase (RNR) catalyzes the first committed reaction in DNA synthesis. Most of what we know about RNR regulation comes from studies with cultured cells and with purified proteins. In this study, Tran et al. use Cre-Lox technology to inactivate RNR large subunit expression in heart and skeletal muscle of mouse embryos. Analysis of these mutants paints a picture of dNTP regulation in whole animals quite different from that seen in studies of purified proteins and cultured cells.
- Two phosphoribosyltransferases in the purine salvage pathway exhibit exquisite substrate specificity despite the chemical similarity of their distinct substrates, but the basis for this discrimination was not fully understood. Ozeir et al. now employ a complementary biochemical, structural, and computational approach to deduce the chemical constraints governing binding and propose a distinct mechanism for catalysis in one of these enzymes, adenine phosphoribosyltransferase. These insights, built on data from an unexpected finding, finally provide direct answers to key questions regarding these enzymes and substrate recognition more generally.
- Radical S-adenosylmethionine (SAM) (RS) methylases perform methylation reactions at unactivated carbon and phosphorus atoms. RS enzymes typically abstract a hydrogen from their substrates, generating a substrate-centered radical; class B RS methylases catalyze methyl transfer from SAM to cobalamin and then to a substrate-centered carbon or phosphorus radical. Radle et al. now show that Mmp10, an RS enzyme implicated in the methylation of Arg-285 in methyl coenzyme M reductase, binds a methylcobalamin cofactor required for methyl transfer from SAM to a peptide substrate.
- On the fiftieth anniversary of the discovery of the Ser-His-Asp catalytic triad, perhaps the most unusual variation on the textbook classic is described: An incomplete catalytic triad in a hydrolase is rescued by a chloride ion (Fig. 1). Structural and functional data provide compelling evidence that the active site of a phospholipase from Vibrio vulnificus employs the anion in place of the commonly observed Asp, reminding us that even well-trodden scientific ground has surprises in store.
- The sexes in humans and other animals typically display numerous differences. This belies the fact that the two major hormone classes responsible for these differences, androgens and estrogens, differ only subtly in their chemical backbones. Androgens have a six-carbon nonaromatic ring—the “A ring” (Fig. 1)—in their steroid skeleton, whereas estrogens have an aromatic A ring. Remarkably, a single protein, steroid aromatase (also called estrogen synthase), is the only known enzyme capable of “aromatizing” the A ring in androgens such as testosterone and androstenedione to produce estrogens such as estradiol and estrone.
- Sitting down to the task of writing, I found my pen drifting inexorably to a personal recollection of the metaphorical transcontinental road that I had traveled to become a scientist, instead of reviewing a facet of our scientific contributions. Factors that prepared me for my improbable journey in an era when international calls were operator-assisted and unaffordable and the internet was the stuff of science fiction were my family’s love and the sheltered environment of my all-girls school and college experiences, which nurtured my self-confidence.
- I learned biochemistry from P. Boon Chock and Earl Stadtman while working on the regulation of Escherichia coli glutamine synthetase as a postdoctoral fellow at the National Institutes of Health. After becoming a tenured scientist at the same institute, my group discovered, purified, and cloned the first three prototypical members of the phospholipase C family and uncovered the mechanisms by which various cell-surface receptors activate these enzymes to generate diacylglycerol and inositol 1,4,5-trisphosphate.