What is the 21st Essential Amino Acid? (It's Selenocysteine)

January 2, 2026 •

3 min read

In 1986, the discovery that the UGA stop codon could direct the incorporation of selenium, in the form of selenocysteine, into proteins revolutionized genetics. This unique amino acid, known as selenocysteine, stands apart from the 20 standard protein building blocks due to its complex biosynthesis and crucial function in a select group of proteins.

Quick Summary

The 21st essential amino acid is selenocysteine, which is critical for human health and is incorporated into proteins called selenoproteins. Its synthesis and integration into proteins during translation is a complex process controlled by special genetic signals, unlike the standard 20 amino acids. A specific genetic element known as a SECIS directs a UGA stop codon to code for selenocysteine instead of ending protein synthesis.

Key Points

Name and Discovery: Selenocysteine is the 21st amino acid, discovered in 1974, with its genetic coding elucidated in the 1980s.
Unique Genetic Coding: Unlike the standard 20, selenocysteine is encoded by the UGA stop codon, but only when a special mRNA signal, the SECIS element, is present.
Superior Reactivity: It has a lower pKa and higher nucleophilicity than cysteine, enhancing its function in catalytic redox reactions.
Essential Nutrient Dependency: Since selenocysteine contains selenium, its synthesis depends on an adequate dietary intake of this essential trace mineral.
Vital Selenoproteins: It is a key component of selenoproteins, such as glutathione peroxidases and thioredoxin reductases, which are crucial for antioxidant defense and metabolism.
Health Significance: Impaired selenocysteine synthesis due to selenium deficiency or genetic mutations can lead to serious health issues.
Unique Synthesis Path: Selenocysteine is synthesized directly on its specific tRNA (tRNASec) from serine, not from a free amino acid pool.

Understanding Selenocysteine: The Unique 21st Amino Acid

While most people are familiar with the 20 standard amino acids that form the building blocks of proteins, scientific discovery has revealed two additional genetically coded amino acids: selenocysteine and pyrrolysine. Among these, selenocysteine is often referred to as the 21st essential amino acid due to its profound importance in human health. Unlike other amino acids, selenocysteine is not freely available in the cellular pool but is synthesized directly on its transfer RNA (tRNA) using selenium derived from the diet. This dependence on the trace element selenium makes it an essential dietary component for humans to produce functional selenoproteins.

The Genetic Codon Recoding Mechanism

Selenocysteine is unique because it is specified by the UGA codon, which typically signals the end of protein synthesis. To incorporate selenocysteine, a complex 'translational recoding' system is used, particularly in eukaryotes (like humans).

This process requires:

A specialized transfer RNA (tRNASec) to carry selenocysteine.
A Selenocysteine Insertion Sequence (SECIS) hairpin structure in the mRNA.
Specific proteins like SECIS-binding protein 2 (SBP2) and elongation factor EFsec to guide incorporation at the UGA codon.

This system ensures selenocysteine is inserted correctly. Low selenium levels disrupt this, leading to non-functional proteins.

The Unique Function of Selenocysteine

Selenocysteine's importance stems from its chemical properties. It is a selenium analog of cysteine. Replacing sulfur with selenium makes selenocysteine more reactive, with a lower pKa (~5.2) compared to cysteine (~8.3). This higher reactivity makes it crucial for the active sites of many selenoenzymes involved in antioxidant defense. For instance, glutathione peroxidase enzymes rely on selenocysteine for detoxifying reactive oxygen species. Proper selenocysteine function is vital for protecting cells from oxidative stress.

Selenoproteins and Their Importance

Proteins containing selenocysteine are called selenoproteins. Humans have 25 known selenoproteins involved in various critical functions, including antioxidant defense, thyroid hormone metabolism, immune responses, and other metabolic processes.

Examples of selenoproteins include:

Glutathione peroxidases (GPx): Protect against oxidative damage.
Thioredoxin reductases (TrxR): Regulate cellular signaling and growth.
Iodothyronine deiodinases (DIO): Regulate thyroid hormone activity.

Selenocysteine vs. Cysteine: A Comparative Look


Feature	Selenocysteine	Cysteine
Defining Atom	Selenium (Se)	Sulfur (S)
Genetic Codon	UGA (Requires SECIS element)	UGU/UGC
pKa of Side Chain	~5.2 (deprotonated at physiological pH)	~8.3 (protonated at physiological pH)
Reactivity	Higher nucleophilicity and faster redox reactions	Lower nucleophilicity and less reactive in redox
Metabolic Cost	High; requires a dietary source of selenium and specialized machinery	Lower; can be synthesized by the body in most cases
Primary Function	Active site of selenoenzymes for potent redox catalysis	Structural stability and redox buffering through disulfide bonds

The Health Implications of Selenocysteine

Selenocysteine is essential for health. Selenium deficiency impairs selenoprotein function, leading to various health issues. The necessity of selenocysteine is shown by its indispensability in animal models. Impaired selenoprotein function is linked to conditions like cardiovascular disease, cancer, and neurological disorders.

Conclusion: The Importance of a Non-Standard Amino Acid

Selenocysteine, the 21st essential amino acid, is a unique case in genetics. Its complex insertion mechanism allows organisms to utilize selenium for superior biological functions through selenoproteins. This highlights the intricate nature of biochemistry and provides insights into nutrition, disease, and the mechanisms of life. You can find more information about selenocysteine's significance in human health(https://researchfeatures.com/amino-acid-selenocysteine/).

Summary of Main Points

Selenocysteine is the 21st amino acid incorporated into proteins via a specialized genetic process.
It is coded by the UGA stop codon, requiring a SECIS element and specific factors to prevent premature termination.
Selenocysteine is more reactive than cysteine, making it vital for potent redox catalysis.
Selenoproteins are critical for human health, involved in antioxidant defense and metabolism.
Sufficient dietary selenium is necessary for selenocysteine and selenoprotein function.

Frequently Asked Questions

The 20 standard proteinogenic amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

Selenocysteine is not standard because it requires a complex recoding mechanism involving a special mRNA hairpin (SECIS element) and specific proteins to be inserted into a growing protein chain. Its synthesis and incorporation are exceptions to the general translation process.

Selenium is a crucial component of selenocysteine, replacing the sulfur atom found in cysteine. The presence of selenium gives selenocysteine unique chemical properties, such as enhanced reactivity, which are essential for the catalytic function of many selenoproteins.

Yes, selenocysteine is essential for human life because it is required for the synthesis of critical selenoproteins that protect against oxidative stress, regulate thyroid hormones, and play other vital roles. Studies in mouse models have shown that a lack of selenocysteine can be embryonically lethal.

The UGA codon is recoded to insert selenocysteine by a specific system involving a selenocysteine insertion sequence (SECIS) in the mRNA, a special tRNA (tRNASec), and dedicated elongation factors that guide the incorporation process.

Yes, another rare, genetically encoded amino acid is pyrrolysine (the 22nd amino acid), which is found in certain archaea and bacteria but not incorporated into proteins by humans.

A selenium deficiency can impair the synthesis of functional selenoproteins, as the body cannot produce selenocysteine. This can lead to increased oxidative stress and dysregulation of various metabolic and protective pathways, impacting overall health.