Which is the 21st amino acid?: Unveiling Selenocysteine

With only 25 selenoproteins encoded in the human genome, the question of which is the 21st amino acid points to a rare but essential component of life. This unique amino acid, selenocysteine, adds a fascinating layer to our understanding of protein synthesis and genetic recoding.

Quick Summary

Selenocysteine is the 21st genetically encoded amino acid, incorporated into proteins through a special recoding of the UGA stop codon using unique mRNA signals and dedicated protein factors.

Key Points

• Identity: The 21st amino acid is selenocysteine (Sec), a rare but genetically encoded building block of proteins.

• Genetic Code Exception: Unlike standard amino acids, selenocysteine is encoded by the UGA codon, which typically functions as a stop signal.

• Unique Mechanism: A specialized mRNA element (SECIS) and dedicated proteins are required to recode the UGA codon for selenocysteine insertion.

• Biological Function: Selenocysteine is critical for the function of selenoproteins, which play key roles in antioxidant defense and thyroid hormone regulation.

• Chemical Nature: Selenocysteine is a cysteine analog with a selenium atom instead of sulfur, giving it enhanced reactivity beneficial for certain enzymatic activities.

• Not a Modification: Selenocysteine is incorporated during translation, not added later, solidifying its status as a genetically encoded amino acid.

Introduction to Selenocysteine, the 21st Amino Acid

For decades, biochemistry textbooks taught that there were 20 standard, proteinogenic amino acids. The discovery of selenocysteine in 1974 challenged this long-held view, revealing that the genetic code, while seemingly rigid, holds a fascinating exception. Selenocysteine (Sec) is a direct analog of cysteine, with an atom of selenium replacing the typical sulfur atom. This substitution dramatically alters its chemical properties, making it a more powerful nucleophile and an integral part of vital enzymes. Its unique nature lies not only in its composition but also in its biosynthesis and incorporation into proteins, which requires a complex and highly regulated mechanism known as translational recoding.

The Unique Mechanism of Genetic Recoding

Unlike the 20 standard amino acids, which have a direct codon-tRNA relationship, selenocysteine is encoded by a UGA codon, which typically serves as a 'stop' signal for protein synthesis. To prevent premature termination and ensure selenocysteine is inserted where needed, a sophisticated cellular machinery has evolved across all domains of life. This machinery relies on several key components working in concert:

• The UGA Codon: While often a stop signal, when part of a selenoprotein-encoding mRNA, it is reinterpreted as a command to insert selenocysteine.
• The SECIS Element: A specific mRNA hairpin-loop structure, the Selenocysteine Insertion Sequence (SECIS), is located in the 3' untranslated region (3' UTR) in eukaryotes, or closer to the UGA codon in bacteria. This element is the key signal that directs the recoding event.
• tRNA${^{Sec}}$: A specialized tRNA molecule exists specifically for selenocysteine. It is first charged with serine by the seryl-tRNA synthetase and then enzymatically converted to selenocysteine on the tRNA. This is a departure from the typical amino acid synthesis pathway.
• Specialized Elongation Factors: The normal elongation factors that deliver tRNAs to the ribosome cannot handle the tRNA${^{Sec}}$. Instead, specialized factors (e.g., SelB in bacteria, eEFSec in eukaryotes) are required to deliver the Sec-tRNA${^{Sec}}$ to the ribosome in a process mediated by the SECIS element and other associated binding proteins.

The Critical Roles of Selenoproteins

Proteins that contain selenocysteine are known as selenoproteins. Despite their relatively low number, these enzymes play crucial roles in cellular function, particularly in redox homeostasis. The presence of the more reactive selenocysteine residue in their active sites provides a catalytic advantage over their cysteine-containing counterparts. In humans, there are 25 known selenoproteins involved in a wide array of biological processes.

Key functions of human selenoproteins include:

• Antioxidant defense: Enzymes like glutathione peroxidases (GPx) and thioredoxin reductases (TrxR) use selenocysteine to efficiently neutralize reactive oxygen species, protecting cells from oxidative stress.
• Thyroid hormone metabolism: Iodothyronine deiodinases (DIO) regulate the activation and deactivation of thyroid hormones, a process critical for development and metabolic regulation.
• Selenium transport: Selenoprotein P (SelP) is a unique selenoprotein with multiple selenocysteine residues that functions to transport selenium throughout the body.

Selenocysteine vs. Pyrrolysine: The 21st and 22nd Amino Acids

While selenocysteine is widely recognized as the 21st amino acid, it is important to note that a 22nd genetically encoded amino acid, pyrrolysine (Pyl), has also been identified in some archaea and bacteria. Both represent fascinating examples of genetic code expansion, but they differ in their origin and mechanism.

Feature	Selenocysteine (21st Amino Acid)	Pyrrolysine (22nd Amino Acid)
Genetic Code Expansion	Occurs by recoding the UGA stop codon	Occurs by reassigning the UAG stop codon
Incorporation Machinery	Requires a special SECIS element and dedicated factors (eEFSec, SelB)	Requires pyrrolysyl-tRNA synthetase (PylRS) and tRNA${^{Pyl}}$
Biosynthesis	Synthesized on its tRNA from a serine precursor	Synthesized from two lysine residues, then attached to its tRNA
Occurrence	Found in all three domains of life	Found primarily in some methanogenic archaea and a few bacteria

Conclusion

Selenocysteine, the 21st amino acid, stands as a remarkable testament to the intricate and flexible nature of the genetic code. Its unique and complex synthesis and incorporation mechanism, which hijacks a stop codon, enables the production of a crucial class of enzymes vital for redox biology and overall health. Studying selenocysteine and its corresponding selenoproteins continues to provide significant insights into molecular biology, evolution, and human health, paving the way for potential therapeutic developments targeting selenoprotein pathways. For further reading, an authoritative resource on the biosynthesis and decoding of selenocysteine can be found at the National Institutes of Health: Synthesis and decoding of selenocysteine and human health.

Key Factors for Selenocysteine Synthesis

• Synthesis on tRNA: Selenocysteine is not synthesized in a free form; instead, it is synthesized directly on its dedicated tRNA molecule from a serine precursor.
• The Role of Selenium: The incorporation of selenium, an essential trace element, is crucial for the formation of selenocysteine.
• UGA Codon Reassignment: The stop codon UGA is specifically recoded to incorporate selenocysteine, a process known as translational recoding.
• The SECIS Element: An mRNA hairpin structure, the SECIS element, acts as the key signal to direct the ribosome to insert selenocysteine rather than terminate translation.
• Specialized Machinery: Dedicated elongation factors and other proteins are required to deliver the selenocysteine-charged tRNA to the ribosome, ensuring precise incorporation.
• Catalytic Advantage: The replacement of sulfur with selenium in selenocysteine gives selenoproteins enhanced catalytic activity, particularly in redox reactions.

Frequently Asked Questions

Question: Why is selenocysteine called the 21st amino acid and not just a modification? Answer: Selenocysteine is considered the 21st genetically encoded amino acid because its insertion into a protein is a co-translational event directly programmed by a codon (UGA), rather than being added as a post-translational modification after the protein is synthesized.

Question: How does the cell know when to insert selenocysteine instead of stopping translation? Answer: The cell uses a specific mRNA sequence and structural element called the Selenocysteine Insertion Sequence (SECIS). This hairpin-loop structure, located downstream of the UGA codon, works with specialized proteins to signal the ribosome to insert selenocysteine instead of stopping.

Question: What is the key chemical difference between selenocysteine and cysteine? Answer: The primary difference is the replacement of a sulfur atom in cysteine with a selenium atom in selenocysteine. This change makes selenocysteine a stronger nucleophile and increases its reactivity, which is advantageous for certain enzymatic functions.

Question: Is selenocysteine essential for human life? Answer: Yes, selenocysteine is essential for mammals, including humans. It is a critical component of 25 human selenoproteins that perform vital functions, particularly in antioxidant defense and thyroid hormone metabolism.

Question: What are some examples of selenoproteins in the human body? Answer: Notable examples of human selenoproteins include glutathione peroxidases, which protect against oxidative damage, and iodothyronine deiodinases, which are involved in thyroid hormone regulation.

Question: Is selenocysteine the only other genetically encoded amino acid besides the standard 20? Answer: No, a 22nd genetically encoded amino acid, pyrrolysine (Pyl), has also been discovered. It is encoded by the UAG stop codon in certain archaea and bacteria, and its incorporation mechanism differs from selenocysteine's.

Question: How is selenocysteine toxicity prevented in the cell? Answer: The high reactivity of selenocysteine means it could be damaging if freely available. The cell prevents this by not maintaining a free pool of selenocysteine. Instead, it is synthesized directly on its tRNA, chaperoned to the ribosome, and incorporated into proteins in a highly controlled manner.

Frequently Asked Questions

How is selenocysteine different from other amino acids?

Selenocysteine's main difference lies in its composition, featuring selenium instead of sulfur, and its unique genetic encoding. It is inserted into proteins by recoding a stop codon, a process unlike that for any of the 20 standard amino acids.

Is selenium a mineral or a vitamin?

Selenium is an essential trace mineral for humans and many other organisms. It is not a vitamin but is an essential dietary component required for the proper function of selenoproteins.

Are there more than 21 amino acids?

Yes, while selenocysteine is the 21st, another genetically encoded amino acid, pyrrolysine (the 22nd), has been discovered. There are also many post-translationally modified amino acids, but these are altered after the protein is synthesized, not encoded directly by the genetic code.

How is selenocysteine incorporated at the correct site in a protein?

The accurate incorporation depends on a specific mRNA sequence called the Selenocysteine Insertion Sequence (SECIS) and specialized proteins. These factors ensure that the UGA codon is interpreted as selenocysteine only when the SECIS element is present.

Why is selenocysteine considered important for human health?

As part of selenoproteins, selenocysteine is crucial for antioxidant defense, regulating thyroid hormone activity, and ensuring proper selenium transport. Mutations affecting selenoprotein function have been linked to various diseases.

How does the cell prevent the UGA codon from terminating the translation of selenoproteins?

The SECIS element, along with a specialized elongation factor (eEFSec) and other binding proteins, effectively competes with the termination machinery that would normally recognize a UGA stop codon. This leads to the correct reading of UGA as selenocysteine.

Can selenocysteine be found in all living organisms?

No, while it is found across all three domains of life (Bacteria, Archaea, and Eukarya), it is not universal. Some organisms, like higher plants and most fungi, do not possess the machinery for selenocysteine synthesis.