22.2: Biosynthesis of Amino Acids (2025)

Introduction

By the time many students get to the study of amino acid biosynthesis, they have seen so many pathways that learning new pathways for the amino acids seems daunting, even though they can be clustered into subpathways. Most know that from a nutrition perspective, amino acids can be divided into nonessential and essential (need external dietary supplementation) amino acids. These are shown for humans below.

• Nonessential amino acids: Alanine, Asparagine, Aspartate, Cysteine, Glutamate, Glutamine, Glycine, Proline, Serine, Tyrosine
• Essential amino acids: Arginine*, Histidine, Isoleucine, Leucine, Lysine, Methionine*, Phenylalanine*, Threonine, Tryptophan, Valine

Three of the essential amino acids can be made in humans but need significant supplementation. Arginine is depleted in processing through the urea cycle. When cysteine is low, methionine is used to replace it so its levels fall. If tyrosine is low, phenylalanine is used to replace it.

The amino acids can be synthesized from glycolytic and citric acid cycle intermediates as shown in Figure \(\PageIndex{1}\)

Figure \(\PageIndex{1}\): Summary amino acid synthesis from glycolytic and TCA intermediates

For this chapter subsection, we will provide only the basic synthetic pathways in abbreviated form without going into mechanistic or structural details (likely to the relief of readers and authors alike!)

Amino acid synthesis from glycolytic intermediates

TCA Intermediates

Summary

In this chapter, we integrate and summarize the biosynthetic pathways that produce the twenty standard amino acids, emphasizing how central metabolic intermediates from glycolysis and the tricarboxylic acid (TCA) cycle serve as key starting points. The amino acids are grouped into nonessential and essential categories, with the understanding that in humans some “conditionally essential” amino acids (such as arginine, methionine, and tyrosine) require supplementation under certain physiological conditions.

Key Concepts Covered:

• Central Carbon Metabolism as a Precursor Source:
  Glycolytic intermediates (e.g., glucose-6-phosphate, 3-phosphoglycerate, and phosphoenolpyruvate) and TCA cycle intermediates (e.g., α‑ketoglutarate and oxaloacetate) provide the carbon skeletons for amino acid synthesis. This chapter demonstrates the elegant link between energy metabolism and the generation of biosynthetic precursors.

• Pathways Originating from Glycolytic Intermediates:

  • From Glucose-6-Phosphate: Histidine is synthesized via a pathway that starts from a phosphorylated ribose derivative.
  • From 3‑Phosphoglycerate: Serine is produced and further serves as a precursor for glycine and cysteine.
  • From Phosphoenolpyruvate: The aromatic amino acids—tryptophan, phenylalanine, and tyrosine—are synthesized via the shikimate pathway up to chorismate, from which distinct branch pathways lead to each aromatic amino acid.

• Pathways Originating from Pyruvate:
  Alanine is formed directly from pyruvate by transamination, while the branched‐chain amino acids (valine, leucine, and isoleucine) are generated through a series of reactions involving pyruvate condensation and further modifications.

• TCA Cycle-Derived Pathways:

  • From α‑Ketoglutarate: Glutamate is synthesized by transamination and serves as a hub for the formation of glutamine, proline, and arginine. Arginine’s synthesis is closely linked to the urea cycle.
  • From Oxaloacetate: Aspartate, produced by transamination, is the precursor for several amino acids including asparagine, threonine, methionine, and lysine. Notably, lysine can be synthesized via the diaminopimelic acid (DAP) pathway in plants and bacteria or via the aminoadipic acid pathway in fungi.

• Integration into Overall Metabolism:
  The chapter also highlights that amino acids are not only the building blocks of proteins but are interwoven into energy metabolism. For example, during fasting or stress, when carbohydrates are scarce, amino acids can be catabolized (after removal of their amino groups) to feed into glycolysis or the TCA cycle. This interconversion is critical since, unlike carbohydrates and lipids, proteins cannot be stored in large quantities.

• Systems-Level Perspective:
  A summary graphic (provided by Reactome) encapsulates how amino acid metabolism connects with protein synthesis, urea cycle, and various other metabolic pathways, underscoring the central role of amino acids in both anabolic and catabolic processes.

Conclusion:

This chapter provides a cohesive overview of the multiple biosynthetic routes leading to amino acids, emphasizing the central role of glycolytic and TCA cycle intermediates as precursors. Understanding these pathways is crucial not only for grasping the fundamentals of cellular metabolism but also for appreciating how alterations in amino acid biosynthesis can affect overall metabolic homeostasis in both health and disease.

These learning goals and the summary serve to prepare you to:

• Trace the Carbon Flow: Map how central metabolic intermediates are diverted into specific amino acid biosynthetic pathways.
• Differentiate Pathways: Distinguish between the different precursor sources and understand the unique steps leading to various amino acid classes.
• Integrate Metabolic Networks: Appreciate how amino acid synthesis is interconnected with energy metabolism and nitrogen balance, which is essential for overall cellular function.
• Apply Biochemical Principles: Utilize principles such as transamination, redox reactions, and metabolic regulation in the context of amino acid biosynthesis.