Cover story

Glycosaminoglycan polysaccharides are complex in structure, length and charge, and this complexity has hampered the characterization of their biological activity. Chondroitin sulfates are sulfated glycosaminoglycans that modify proteins in the extracellular matrix. To examine the role of structure and charge on biological function, Gama et al. generated short chains of the basic chondroitin sulfate repeating disaccharide unit carrying different sulfation patterns. The authors found that the precise position of the sulfate groups dictates their ability to bind two neuronal growth factors and thereby modulate neuronal outgrowth, which suggests the existence of a “sulfation code”: much as the genetic code specifies the position of amino acids to form distinct proteins, the sulfation code may specify the locations of sulfate groups to regulate protein-protein interactions. [Letters, p. 467 ; News & Views, p. 449 ] MB

How to make a DIFference

The slime mold Dictyostelium discoideum normally exists as an amoeba, but under stressful conditions individual amoebas coalesce into a migratory slug-like entity. This multicellular pseudoplasmodium can be induced to differentiate into a fruiting body that bears a spore-containing pod atop an extended stalk. Small molecules called differentiation-inducing factors (DIFs) help coordinate this phenotypic transformation. Austin et al. now provide insight into the biosynthesis of one of these signaling molecules: DIF-1. Using bioinformatic, biochemical and structural approaches, the authors show that Steely2 proteins, which are hybrid type I fatty acid synthase–type III polyketide synthase enzymes, catalyze the biosynthesis of the phloroglucinol skeleton of DIF-1. D. discoideum strains lacking Steely2 could not produce DIF-1, which supports the in vivo role of these hybrid enzymes in the biogenesis of DIF signaling molecules. [Articles, p. 494 ; News & Views, p. 451 ] TLS

NOvel ceruloplasmin activity

The cellular signaling molecules nitric oxide (NO) and nitrite (NO2−) can be interconverted in vivo. NO is generated from nitrite through several mechanisms, including enzymatic reduction by xanthine oxidoreductase and reaction with deoxyhemoglobin. Much less is known about the reverse reaction: biological formation of nitrite from NO. Shiva et al. now show that the multicopper oxidase ceruloplasmin is a physiological NO oxidase. The authors found that purified ceruloplasmin increases plasma nitrite formation, whereas depletion of ceruloplasmin reduces nitrite formation. In addition, plasma from humans with aceruloplasminemia, a disease caused by a mutation in the gene encoding ceruloplasmin, or from ceruloplasmin knockout mice, had lower NO oxidase activity than healthy controls. Compared to controls, the authors found greater liver damage after obstructing liver blood supply in ceruloplasmin knockout mice; this effect was attenuated by injected nitrite, highlighting the physiological importance of nitrite regulation by ceruloplasmin. [Articles, p. 486 ; News & Views, p. 452 ] JK

To diffuse or not to diffuse: that is the kinesin

Eg5 is a motor protein of the kinesin family that can slide apart microtubules of the mitotic spindle. Aside from Eg5's likely involvement in sliding antiparallel microtubules against each other via its plus end–directed nature, little is known about the way this protein functions in spindle organization. Kwok et al. visually monitored single Eg5 molecules and found that Eg5 moves in a stepwise and processive fashion along microtubules. Eg5 movement was either active unidirectional motion or passive one-dimensional diffusion. The Eg5 inhibitor monastrol increased the amount of diffusive movement, which helps explain the ability of this compound to disrupt bipolar mitotic spindles. [Letters, p. 480 ] MB

Radio silence

The tumor suppressor p53 is involved separately in inhibiting cell growth, which protects nontumor p53-expressing cells from genotoxic stress during radiation treatment, and mediating apoptosis, which can contribute to cancer treatment side effects. Strom et al. have identified a new p53 inhibitor, PFTμ, that prevents radiation-induced apoptosis through a pathway that does not affect the radioprotective function of p53. The authors also used PFTμ to dissect the mitochondrial and transactivation branches of the p53 pathway and implicate the mitochondrial branch in radiosensitivity. PFTμ could potentially be used as a cancer therapeutic to protect normal cells during radiation treatment, as cancer cells often lack active p53. [Letters, p. 474 ] MB

Cells in silico

Owing to the inherent redundancy of biological systems, an important approach to treating disease is combination drug therapy, in which compounds specifically targeted to a pair or panel of biological molecules more effectively perform a desired task than do single drugs. A Perspective by Fitzgerald et al. provides an illustrative mathematical treatment of some of the biological networks in which these approaches are necessary and feasible. They report that previous models of dose-response relationships in combination therapy may not accurately reflect the complexity of cellular systems. Instead, predictive models using a systems-biology approach yield reasonable insights into drug interactions. [Perspective, p. 458 ] CG

In This Issue written by Mirella Bucci, Catherine Goodman, Joanne Kotz and Terry L. Sheppard