Which of the following amino acids is considered a non-standard amino acid? A Comprehensive Guide

While most proteins are built from a standard set of 20 amino acids, science has identified over 140 non-proteinogenic types. This guide will help you understand the core differences and answer the question: Which of the following amino acids is considered a non-standard amino acid?

Quick Summary

Explores the fundamental differences between standard and non-standard amino acids. Explains categories like selenocysteine and hydroxyproline, detailing their unique incorporation pathways.

Key Points

• Definition: Non-standard amino acids are any amino acids not incorporated into proteins during standard ribosomal synthesis from a dedicated codon.

• Genetically Encoded Non-Standard: Selenocysteine and pyrrolysine are incorporated during translation by recoding UGA and UAG stop codons, respectively.

• Post-Translational Modification: Amino acids like hydroxyproline are created by modifying a standard amino acid (proline) after it has been incorporated into a protein chain, such as collagen.

• Metabolic Intermediates: Some non-standard amino acids, such as ornithine and citrulline, are never part of proteins but are vital intermediates in metabolic pathways like the urea cycle.

• Diverse Category: The term "non-standard" is a broad classification that includes both amino acids directly built into proteins through special mechanisms and those that are post-synthetically modified or exist only as metabolites.

Defining Standard vs. Non-Standard Amino Acids

In biochemistry, amino acids are the building blocks of proteins. The 20 "standard" or proteinogenic amino acids are those directly encoded by the universal genetic code and incorporated into proteins during ribosomal translation. Any amino acid found in nature that falls outside this core group is classified as a non-standard amino acid. This broad category can be further divided into several types based on how they are produced or incorporated.

Non-standard amino acids can be incorporated into a protein via special genetic mechanisms (like selenocysteine and pyrrolysine) or added through a post-translational modification (PTM) after the protein has been synthesized. Still others exist as intermediates in metabolic pathways but are never incorporated into proteins at all. Understanding these distinctions is key to recognizing why the answer to "which of the following amino acids is considered a non-standard amino acid" is not always straightforward without context.

Genetically-Encoded Non-Standard Amino Acids

Selenocysteine (Sec): The 21st Amino Acid

Selenocysteine is perhaps the most well-known example of a non-standard amino acid that is directly incorporated into proteins during translation. Unlike the standard 20, selenocysteine is not coded by a regular sense codon. Instead, it is encoded by the UGA codon, which typically functions as a stop signal. To enable its insertion, a special sequence in the mRNA called a Selenocysteine Insertion Sequence (SECIS) is required. This complex mechanism allows certain proteins, known as selenoproteins, to incorporate selenium, which is essential for certain enzymatic functions, particularly those related to antioxidant activity. The synthesis of selenocysteine occurs directly on its transfer RNA (tRNA) and is not a post-translational event.

Pyrrolysine (Pyl): The 22nd Amino Acid

Discovered in certain archaea and bacteria, pyrrolysine is another fascinating example of a non-standard amino acid that is directly encoded during protein synthesis. It is directed by the UAG amber stop codon and relies on a specific pyrrolysine-tRNA synthetase (PylRS) and its cognate tRNA. This amino acid is primarily found in enzymes involved in the metabolism of methylamines in methanogenic archaea. Its discovery further demonstrated that the genetic code is not as universally fixed as once thought, but contains rare exceptions for specialized biological functions.

Post-Translationally Modified Amino Acids

Many non-standard amino acids found in proteins are actually modifications of one of the standard 20 amino acids. These changes occur after the protein has been synthesized on the ribosome and are crucial for the protein's final function and structure.

Hydroxyproline (Hyp)

Hydroxyproline is a major component of collagen, the most abundant structural protein in animals. It is formed by the hydroxylation of proline residues that have already been incorporated into the nascent collagen polypeptide chain. This modification, which requires vitamin C as a cofactor, significantly increases the stability of the collagen triple helix, giving connective tissues their strength and structure. Without sufficient vitamin C, hydroxylation fails, leading to unstable collagen and the condition known as scurvy.

Other Post-Translational Modifications

• Phosphorylation: The addition of a phosphate group, typically to serine, threonine, or tyrosine residues, plays a critical role in regulating enzyme activity.
• Methylation: The addition of a methyl group to amino acids like lysine and arginine is a key epigenetic and regulatory modification.
• Glycosylation: The attachment of carbohydrate molecules to asparagine, serine, or threonine is important for cell signaling and protein folding.

Metabolic Intermediates: Non-Proteinogenic Amino Acids

A large group of non-standard amino acids are those that exist as intermediates in metabolic pathways but are never incorporated into proteins. These molecules are essential for metabolism but are not part of the genetic coding machinery.

• Ornithine and Citrulline: These two amino acids are vital intermediates in the urea cycle, which is responsible for detoxifying and removing ammonia from the body. They are never found in synthesized proteins.
• GABA (gamma-aminobutyric acid): This is a major inhibitory neurotransmitter in the mammalian central nervous system, produced by the decarboxylation of glutamic acid.
• Homocysteine: A homologue of cysteine, homocysteine is an intermediate in methionine metabolism and high levels are associated with health risks.

Comparison of Standard and Non-Standard Amino Acids

Feature	Standard Amino Acids	Genetically-Encoded Non-Standard Amino Acids	Post-Translationally Modified Amino Acids	Metabolic Intermediate Non-Standard Amino Acids
Example	Alanine, Leucine	Selenocysteine (Sec), Pyrrolysine (Pyl)	Hydroxyproline (Hyp), Phosphoserine	Ornithine, Citrulline, GABA
Incorporation	Incorporated directly during ribosomal translation, using standard codons (e.g., GCU for Alanine).	Incorporated during ribosomal translation, but via recoding of stop codons (UGA or UAG).	Formed by modifying a standard amino acid after it has been incorporated into a protein chain (post-translational modification).	Never incorporated into protein chains. Act as free amino acids in metabolic cycles.
Genetic Code	Directly specified by the universal genetic code, with dedicated sense codons.	Special mechanisms override stop codons, requiring unique mRNA sequences (SECIS) or tRNAs.	Not directly encoded by the genetic code; relies on specific enzymes acting on the completed protein.	Not encoded by the genetic code. Often produced or consumed within cellular metabolic pathways.
Function/Role	Building blocks for the vast majority of proteins, determining protein structure and function.	Provide specialized catalytic functions, such as the antioxidant roles of selenoproteins.	Essential for modifying protein function, stability, and structure, such as stabilizing collagen.	Serve as crucial components in metabolic cycles (e.g., urea cycle) or as signaling molecules (e.g., neurotransmitters).

Conclusion: Which is a non-standard amino acid?

Based on the distinctions outlined, it is clear that many amino acids can be classified as non-standard. The term encompasses everything from genetically encoded but non-canonical residues like selenocysteine to post-translational modifications like hydroxyproline and metabolic intermediates like ornithine. Therefore, in the context of a multiple-choice question, a correct answer could be Selenocysteine, Hydroxyproline, or Ornithine, depending on the options provided. The critical factor for determining if an amino acid is non-standard lies in its synthesis and incorporation mechanism—whether it is directly encoded by the standard genetic code or produced through other means.

For more in-depth information, the National Institutes of Health has detailed articles on selenocysteine biosynthesis.

Frequently Asked Questions

What is the main difference between a standard and a non-standard amino acid?

The main difference lies in how they are incorporated into proteins. Standard amino acids are directly encoded by the universal genetic code during translation, while non-standard amino acids are either incorporated through special genetic mechanisms or are the result of post-translational modifications, or are metabolic intermediates never incorporated at all.

Is selenocysteine the only genetically encoded non-standard amino acid?

No, selenocysteine is often referred to as the 21st amino acid, but pyrrolysine is another example. Pyrrolysine is a 22nd amino acid encoded by the UAG stop codon in specific archaea and bacteria.

How is hydroxyproline formed and what is its function?

Hydroxyproline is formed by the enzyme-catalyzed hydroxylation of proline residues after the proline has already been incorporated into a polypeptide chain, specifically in collagen. It is essential for stabilizing the collagen triple helix.

What is the role of non-standard amino acids like ornithine and citrulline?

Ornithine and citrulline are metabolic intermediates that play a crucial role in the urea cycle, which converts toxic ammonia into urea for excretion. They are not found in proteins.

Can non-standard amino acids be found within protein structures?

Yes, some non-standard amino acids are found in proteins. This can happen in two ways: either through special genetic recoding during translation (e.g., selenocysteine) or by post-translational modification of a standard amino acid residue already in the protein (e.g., hydroxyproline).

Why is selenocysteine sometimes called the 21st amino acid?

Selenocysteine is called the 21st amino acid because it is directly encoded by a specific codon (UGA) and incorporated into proteins during ribosomal translation, expanding upon the traditional set of 20 standard amino acids.

Are non-essential amino acids the same as non-standard amino acids?

No, they are different classifications. Non-essential amino acids are a subset of the standard 20 amino acids that a body can synthesize, so they don't have to come from the diet. Non-standard amino acids are not part of the core 20 standard, proteinogenic amino acids.