Nature Structural Biology pp 602 - 608

There are times when cell death is a good thing. During viral infection, for example, cell death can thwart an invading virus by depriving it of a hospitable place to thrive. Likewise, unwanted cells are destroyed during development, metamorphosis, and tissue turnover. This orderly process is known as programmed cell death or apoptosis. Cell death figures prominently in the functioning of the immune and nervous systems. Apoptosis is also an important mechanism for eliminating cancerous cells.

While a variety of signals can trigger apoptosis, there are also a number of inhibitors of apoptosis. One example of such an inhibitor is a human protein known as survivin that is expressed at the start of cell division. High levels of survivin are found in the developing embryo and in many common human cancers, including lung, colon, pancreas, prostate, and breast cancer. This finding makes it a novel target for cancer therapy.

To try to understand how this protein inhibits apoptosis and promotes tumor cell survival, Joseph Noel, of the Structural Biology Laboratory at The Salk Institute for Biological Studies in La Jolla, California, USA, and his coworkers have now solved its structure by X-ray crystallography.

It seems that two copies of the protein must come together for survivin to function and the structure shows just such an interaction. Thus the region of contact between the two copies of the protein might be an attractive target for the development of small molecules that could disrupt this interaction and thereby prevent tumor survival by allowing cell death to proceed.

Nature Structural Biology pp 560 - 564

Many of the chemical compounds known as arylamines or arylhydrazines are potential carcinogens, and sometimes their activation or, conversely in some cases, their detoxification depends on the action of a family of enzymes called the N-acetylatransferases (NATs). These enzymes catalyze the attachment of a particular chemical group—an acetyl group—to a substrate molecule. Some mutations in the human NAT genes cause this reaction to slow down and have been shown to correlate with the occurrence of bladder cancer. Therefore, how NATs recognize their substrates and catalyze the acetyl group transfer reaction are of considerable medical interest.

Not all arylhydrazines that are inactivated by NATs are carcinogenic—some are actually useful drugs. The drug isoniazid, which has been used as the first line of defense against tuberculosis since the early 1950s, is a key example. Recently, a homolog of NAT has been discovered in the genome of Mycobacterium tuberculosis, the organism that causes tuberculosis, and it has been shown that the level of NAT present in the bacterium affects its sensitivity to this drug. Understanding the catalytic mechanism of isoniazid inactivation by NAT could help in designing new anti-tuberculosis drugs that are not as easily inactivated.

Now, Martin Noble, at Oxford University in the UK, and his colleagues have determined the structure of NAT from the bacterium Salmonella typhimurium by X-ray crystallography. Because the amino acid sequences of the NATs from Salmonella and Mycobacterium are similar, the structure of NAT from one organism provides information on that of the other. This structure is an excellent starting point for understanding how NATs act on their arylamine and hydrazine targets.

Nature Structural Biology pp 542 - 546

In 1902, shortly after the rediscovery of Mendel's work, Archibald Garrod, a practicing physician at the Hospital for Sick Children in London, England, proposed that the disease alkaptonuria in humans was inherited according to the genetic laws proposed by Mendel. In so doing, he identified the first "inborn error of metabolism". Like Mendel's work, this finding was largely ignored until the Nobel prize winning work of Beadle and Tatum (Physiology or Medicine, 1958) who proposed the one gene, one enzyme hypothesis, which states that each gene is responsible for directing the building of a single, specific enzyme.

We now know that alkaptonuria is a defect in the enzyme homogentisate dioxygenase (HGO). In humans, the degradation of the amino acids phenylalanine and tyrosine requires six enzymes, and HGO is one of them. When this enzyme is defective, there is a buildup of degradation products that leads to a blackening of the urine and the presence of deposits in connective tissues, resulting in degenerative arthritis. At least 20 different types of mutations in the gene for HGO are known to cause alkaptonuria.

Now, David Timm, of the Indiana University School of Medicine in the USA, and his coworkers present the first structure of human HGO, solved by X-ray crystallography. They find that six copies of the HGO protein associate together into one large 'hexamer', and that many of the amino acid positions that can be mutated to result in alkaptonuria are located in the regions of contact between the six copies of the protein, where the enzyme's chemical reaction appears to take place.