Reproductive biology: enhancing sperm vitality

During artificial insemination procedures mammalian sperm cells are particularly vulnerable to oxidative damage, which reduces the functional lifespan of sperm and consequently affects fertility. In an article in the October issue of Nature Chemical Biology, researchers report the application of a new hybrid polymer that boosts antioxidant levels in porcine sperm, enhancing both vitality and lifespan. This approach could be applied to increase fertility rates in humans or other mammals, such as rare or endangered species, in which sperm may have to be transported over long distances.

Hybrid polymers containing both antioxidant and targeting elements were designed by Benjamin Davis and colleagues to seek out the surface of mammalian sperm cells. This cell-surface interaction is mediated by a carbohydrate-binding protein that specifically recognizes galactose, a monosaccharide sugar. When the galactose-containing polymer binds to the surface of the sperm-cell, it is transported across the cell membrane, whereupon the antioxidant vitamin E is released. Treated cells had lower oxidative damage, resulting in enhanced lifespan and physiological properties. Using a fluorescence-labeled polymer, the authors were able to visualize sperm cell internalization of galactose-containing polymers. On the other hand, a galactose-free polymer was not internalized, demonstrating that polymer internalization depends on the galactose interaction with the sperm cell surface.

Now, Pezacki and coworkers have used a state-of-the-art microscopy technique called near-field scanning optical microscopy (NSOM) to visualize cell-surface beta-adrenergic receptors of heart cells. Because NSOM has higher resolution than conventional light microscopy, it is possible to visualize individual molecules located on the cell surface. The authors showed that between 15% and 20% of the receptors located on the cell surface were clustered into distinct groups or signalling islands. Using a combination of NSOM and fluorescence microscopy, the authors were able to estimate the density of receptors clustered in the signalling zones. Receptor stimulation produced no change in receptor density, which suggests that the receptors are prearranged into signalling islands.

This work provides a viable approach for enhancing the vitality of porcine sperm. Its further application could potentially enhance fertilization rates in other mammals and provide a useful means to discover new carbohydrate-protein interactions.

Genome mining reveals new natural products

Researchers have discovered a new microbial natural product by a technique called “genome mining,” according to a paper in the October issue of Nature Chemical Biology. Using microbial DNA sequences, the authors predicted the existence and properties of a compound called coelichelin, isolated it from the microbe, and revealed its chemical structure. This technique shows the predictive power of genome mining for uncovering new natural products, which may speed the discovery of new medicines.

In the past, natural products chemists have unearthed many compounds from natural sources that have important medicinal properties. But this process involves laborious purification steps to find a desired small-molecule needle in a metabolite haystack. Gregory Challis and colleagues report a more predictive and streamlined approach based on genome mining. Using genome sequences from Streptomyces coelicolor, the authors identified biosynthetic gene clusters that helped them predict the existence of a previously unknown molecule, which they called coelichelin. Using this insight from genome sequences, the authors isolated coelichelin from the microbe. Further structural detective work revealed that coelichelin is a tetrapeptide, which helps microbes acquire iron ions from their environment under iron-poor conditions. The authors also showed that the biosynthesis of this molecule is more complex than expected; it is produced by a three-component enzyme system working in concert with a separate protein, which is highly unusual for this class of compounds.

This innovative approach to isolating natural products suggests that genome mining may offer an alternative route to identifying new compounds of biological origin.

Nitrite gives a signal

Should you eat another hot dog? A paper in the September issue of Nature Chemical Biologyreports that nitrite--a common additive in foods such as hot dogs--is a built-in signaling molecule that regulates multiple biochemical pathways. The high levels of nitrite resulting from its addition to food have been considered dangerous because they could cause low blood pressure and lead to the production of carcinogenic compounds. Although these high nitrite concentrations have the potential to cause harmful effects to our health, low levels of nitrite have been considered physiologically inert. Recent research however, has suggested that low levels of nitrite could influence physiological processes such as vasodilation -- the dilation of blood vessels.

Martin Feelisch and colleagues have now examined the specific biochemical response to nitrite and shown that levels of protein nitrosylation and nitrosation (the addition of nitric oxide to different positions in proteins) are directly correlated with in vivo nitrite levels. These protein modifications lead to changes in multiple biochemical signaling pathways and gene transcription in vivo. Mechanistic evidence has further suggested that nitrite may be able to modify proteins directly, rather than going through nitric oxide, a well-established signaling molecule.

The team's results uncover new avenues for mechanistic exploration of the physiological roles of nitrite and could have important implications for dietary guidelines for nitrite-containing foods.

Seeing a zebrafish's beating heart

The first high-throughput analysis for organ function in a living vertebrate is reported in the September issue of Nature Chemical Biology. Monitoring organ function in living organisms provides a powerful method for monitoring the effects of potential drugs in vivo. However, automating a high-throughput screen for organ function has been challenging due to the necessity of evaluating the effects of the drugs on individual organisms.

C. Geoffrey Burns and colleagues have developed an automated fluorescence microscopy assay for monitoring the beating heart of a zebrafish. In zebrafish embryos, they labeled the myocardium--the heart's muscular wall--with a green fluorescent tag. Using this transgenic zebrafish, they accurately measured heart rates over a large range of heartbeats per minute. With this method, Burns and colleagues were able to monitor the response of zebrafish to drugs known to affect heart rate, such as tamoxifen.

This research will be an important new tool for developing drugs for heart disease. In addition, the extension of this approach to other physiological parameters will open up new doors for whole-organism phenotype-based screening.

A carbohydrate-antioxidant hybrid polymer reduces oxidative damage in spermatozoa and enhances fertility

C Fleming, A Maldjian, D Da Costa, A K Rullay, D M Haddleton, J St. John, P Penny, R C Noble, N R Cameron & B G Davis

Published online: 4 September 2005 | doi 10.1038/nchembio730

Abstract | Full text | PDF

Genome mining reveals new natural products

S Lautru, R J Deeth, L M Bailey & G L Challis

Published online: 11 September 2005 | doi 10.1038/nchembio731

Abstract | Full text | PDF |

Nitrite gives a signal

N S Bryan, B O Fernandez, S M Bauer, M F Garcia-Saura, A B Milsom, T Rassaf, R E Maloney, A Bharti, J Rodriguez & M Feelisch

Published online: 18 September 2005 | doi 10.1038/nchembio734

Abstract | Full text | PDF |

Seeing a zebrafish's beating heart

C Geoffrey Burns, D J Milan, E J Grande, W Rottbauer, C A MacRae & M C Fishman

Published online: 18 September 2005 | doi 10.1038/nchembio732

Abstract | Full text | PDF |