In Biology 101, students learn the genetic code covers exactly 20 amino acids. It is a number that most students readily repeat and that most biologists rarely, if ever, think to question.
But what if written into the genetic code of many organisms was a previously overlooked coding sequence, or codon, for a 21st amino acid? Who would determine whether this discovery actually met the criteria for a new amino acid? And what would those criteria even be?
That is the situation those who study selenium-containing proteins have faced over the past decade. Selenium, a trace element in the human diet that is incorporated into the active sites of some human proteins primarily in the form of selenocysteine, is currently one of the most hotly studied agents in cancer prevention. According to the National Cancer Institute, there are four phase III cancer prevention trials under way that involve selenium for the prevention of cancers of the prostate, colon, and lung.
In the 1980s, scientists discovered in the model organism Escherichia coli that selenocysteinewhich is structurally similar to cysteine but contains a selenium atom in place of the usual sulfur atomhas its own codon, UGA, in messenger RNA. The plot then thickened when additional work established that E. coli also possesses specialized cellular machinery to synthesize and insert selenocysteine into a forming protein, the same types of accessories needed to process other amino acids. Among this machinery is a transfer RNA that recognizes the UGA codon and an elongation factor that specifically inserts selenocysteine into a forming protein.
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Not So Fast
That might have been the end of the discussion, except that selenocysteine proved an imperfect fit in the universal genetic code. Each of the 64 possible codons spells out a single code word. Whereas multiple codons may encode the same amino acidfor instance, there are eight cases in which a single amino acid has four codonsnone are supposed to speak in more than one word.
The selenocysteine codon, however, turned out to use a two-word vocabulary. In addition to coding for selenocysteine, UGA functions as a stop codon, its predominant command in the genetic code. Interestingly, a two-word codon was not without precedent. Several years ago, scientists found the codon AUG can both initiate protein synthesis and insert methionine into proteins.
Adding to the confusion is the fact that selenocysteine is processed differently than other amino acids. Whereas transfer RNAs typically attach their appropriate amino acid and transport it for packaging into protein, selenocysteines transfer RNA has to wait for some additional chemistry. It attaches a serine, which serves as the backbone for a chemical reaction that then produces selenocysteine.
But, most problematic of all, selenocysteine is not universal in nature, as are the other 20 amino acids. Recent genomic analyses indicate that, although selenocysteine is apparently ubiquitous in people and animals, its presence is hit and miss on other branches of the tree of life. In bacteria, for instance, of the estimated 70 or so genomes that have been sequenced, about 15% make selenocysteine. In archaea, only two of the roughly one dozen sequenced genomes produce it. In higher plants and yeast, selenocysteine is absent.
And yet, in organisms that make selenium-containing proteins, gene-knockout studies show that inactivating the selenocysteine transfer RNA, meaning no selencocysteine is produced, is essential to life. This finding is all the more puzzling because selenoproteins are relatively rare in the genome. Humans, for instance, make perhaps two dozen selenoproteins.
"Theres no mystery why nature has gone to so much effort to get selenium into protein," said Dolph Hatfield, Ph.D., a scientist at the National Cancer Institute and one of the pioneers of modern selenium research. "Selenium is such a good donor of hydrogen ions, and it is completely ionized at [normal blood pH levels]. Sulfur is typically the main atom involved in redox reactions [to control destructive oxygen free radicals], but selenium is so much better at it. So, it seems nature has gone to all of this trouble to incorporate it."
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Lost in Translation
As might have been expected, scientists who study selenium soon started to refer publicly to selenocysteine as "the 21st amino acid." What was not expected was the general silence of their colleagues. "Ive never been challenged about calling selenocysteine the 21st amino acid," said Hatfield, a point that other selenium researchers reiterate.
The lack of debate, however, is misleading. As Hatfield and others noted, many remain unaware that a possible 21st amino acid has emerged in the scientific literature. Others say they do not see the point in revisiting the universal genetic code, even if, as selenocysteine suggests, the power of the paradigm is not 100% accurate.
It also is unclear which, if any, esteemed scientific body holds the authority to settle such fundamental issues. For instance, according to a spokeswoman at the National Academy of Sciences in Washington, D.C., the organization has no panel in place to evaluate such questions. The same holds true for the American Society for Biochemistry and Molecular Biology (ASBMB) in Bethesda, Md.
"This is very much an issue that we would let the to-and-froing of peer review and the development of science kick in," said Peter Farnham, the public affairs officer at ASBMB. "We wouldnt presume to issue any pronouncements in this regard."
As some point out, peer-reviewed scientific journals lack the authority and the mandate to settle such questions. And, despite their encyclopedic and authoritative tones, the authors of textbooks on biochemistry generally try to keep the concepts simple to connect with beginning students.
"The reason that selenocysteine is not mentioned in the initial discussion of amino acids is that it is incorporated in a special way," said Jeremy M. Berg, Ph.D., director of NIHs National Institute of General Medical Sciences, referring to the popular textbook Biochemistry, of which he is a co-author. "UGA codons are normally read the great majority of the time as stop codons, but in special RNA contexts they [code] for selenocysteine. Thus, putting it on the same footing as the main 20 would likely confuse students, many of whom are seeing the material for the first time."
For pragmatic reasons, most selenium researchers say they are disinclined to bring the issue to a head. "Selenocysteine incorporation itself as an amino acid is secondary to the issues of nutrition and what the RDA levels should be," noted Paul R. Copeland, Ph.D., who studies selenocysteine incorporation at the University of Medicine and Dentistry of New Jersey in Piscataway. "That is a huge controversy that probably will continue for the next decade at least, and thats part of the problem. The concepts regarding whether or not selenocysteine is the 21st amino acid is not vitally important to the majority of the selenium field."
Need To Know Biology
This lack of closure, however, can lead to confusion. In the recent sprint to sequence the human genome, scientists at Celera Genomics and the public Human Genome Project programmed their computational gene-annotation software to read the codon TGAthe genomic template for the UGA coding sequence in messenger RNAas a stop codon only. They apparently were unaware of a possible 21st amino acid.
"Some genes encoding selenocysteine-containing proteins were truncated by the annotation programs, which identified parts of selenoprotein open reading frames but terminated them at TGA," said Vadim N. Gladyshev, Ph.D., who studies selenocysteine-containing proteins at the University of Nebraska in Lincoln. "Some selenoproteins were completely missed. For example, if TGA is located at the beginning of a small openreading frame, the programs could not recognize the gene."
Gladyshev said Gregory Kryukov, a postdoc in his laboratory, and colleagues spent a few years developing a special computer program that found all or almost all of the selenoproteins missed by Celera and the Human Genome Project. For its effort, the group published an article last year in the journal Science that reported that 25 selenoprotein genes are present in human DNA.
"To understand the role of selenium in biology and human health, we have to know the identities and functions of all selenium-containing proteins," said Gladyshev. "When we know which proteins contain selenium and what these proteins do in the cell, we can start explaining the biomedical effects of dietary selenium, such as its role in cancer prevention and aging."
Although efforts to settle the 21st amino acid question remain fairly dormant, the issue could still germinate. Gladyshev and Hatfield continue to write frequent review articles on the subject, and Söll will also raise the issue in an upcoming review.
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