Sialic Acid Biosynthesis: A Critical Pathway in Cellular Function and Health

By SWA

Exploring "CRISPR editing of candidate host factors that impact influenza A virus infection"
https://journals.asm.org/doi/10.1128/spectrum.02627-24

Sialic acid biosynthesis refers to the process by which cells produce sialic acids, a family of acidic sugars typically found at the outermost ends of glycan (sugar) chains on the surfaces of cells and proteins. These sugars play a pivotal role in a wide range of biological processes, including cell-cell communication, immune system regulation, and pathogen recognition. Because of their strategic positioning on cell surfaces, sialic acids act as important molecular signals and protectors, influencing both normal physiology and disease states.

Key Steps in Sialic Acid Biosynthesis

The synthesis of sialic acids is a multi-step biochemical process involving several key enzymes and intermediates. Here’s a breakdown of how cells produce these essential molecules:

1. Starting with UDP-GlcNAc (Uridine Diphosphate N-Acetylglucosamine):

The biosynthesis begins with UDP-GlcNAc, a common sugar nucleotide involved in various metabolic pathways. This molecule serves as the initial substrate for the sialic acid biosynthetic pathway.

2. Formation of ManNAc (N-Acetylmannosamine):

The enzyme GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) catalyzes the conversion of UDP-GlcNAc into N-acetylmannosamine (ManNAc). This is a critical regulatory step in the pathway, as GNE activity controls the flow of metabolites into sialic acid production.

3. Conversion to N-Acetylneuraminic Acid (Neu5Ac):

Once ManNAc is formed, it undergoes phosphorylation and is condensed with phosphoenolpyruvate (PEP) to produce N-acetylneuraminic acid (Neu5Ac)—the most common form of sialic acid in humans. The enzyme NANS (N-acetylneuraminic acid synthase) is responsible for catalyzing this reaction.

4. Activation of Sialic Acid:

For sialic acid to be functionally incorporated into glycoproteins and glycolipids, it needs to be activated. The enzyme CMAS (Cytidine Monophosphate N-acetylneuraminic Acid Synthase) converts Neu5Ac into CMP-Neu5Ac (cytidine monophosphate–sialic acid). This activated form is the donor substrate used in subsequent glycosylation reactions.

5. Incorporation into Glycoproteins and Glycolipids:

Finally, sialyltransferases transfer CMP-Neu5Ac to the terminal positions of glycan chains on proteins and lipids within the Golgi apparatus. This step finalizes the process, placing sialic acids where they can perform their critical cellular functions.

Why Is Sialic Acid Important?

Sialic acids serve as more than just structural sugar residues; they are dynamic participants in numerous biological activities. Their roles are essential for maintaining normal cellular operations and protecting the body from external threats.

1. Cell Recognition & Communication:

Sialic acids act like molecular ID tags on cell surfaces, facilitating recognition and communication between cells. This is essential for tissue organization, cellular migration, and the formation of functional organs and systems.

2. Immune System Regulation:

By acting as "self" markers, sialic acids prevent the immune system from mistakenly targeting the body's own cells. They also modulate immune responses, reducing unnecessary inflammation and maintaining immune homeostasis.

3. Pathogen Interaction:

Many pathogens exploit sialic acids to gain entry into host cells. For example, the influenza virus uses a protein called hemagglutinin to bind to sialic acids on respiratory tract cells, facilitating infection. Similarly, certain bacteria recognize sialylated structures to adhere to and invade host tissues.

4. Brain Development & Function:

Sialic acids are abundant in the brain, particularly in molecules called gangliosides (a type of glycolipid). These molecules are vital for neuronal development, synaptic function, and signal transmission. Disruptions in sialic acid metabolism can impair brain development and function, contributing to neurological disorders.

Disorders Related to Sialic Acid Biosynthesis

Mutations in the genes involved in sialic acid biosynthesis can lead to serious metabolic and neuromuscular disorders. While some of these conditions are rare, their impact on affected individuals can be profound.

1. Sialuria:

Sialuria is a rare metabolic disorder caused by mutations in the GNE gene. These mutations result in excessive production and accumulation of free sialic acid within cells. Symptoms may include:

  • Developmental delays
  • Organ enlargement (hepatosplenomegaly)
  • Coarse facial features

The condition is typically diagnosed through genetic testing and the measurement of sialic acid levels in urine.

2. GNE Myopathy (Hereditary Inclusion Body Myopathy):

GNE Myopathy, also known as Hereditary Inclusion Body Myopathy, is a progressive muscle-wasting disorder caused by mutations in the GNE gene. The mutations impair sialic acid production in muscle tissue, leading to:

  • Muscle weakness (particularly in the legs and arms)
  • Difficulty walking or lifting objects
  • No significant involvement of the heart or respiratory muscles

The onset usually occurs in early adulthood, and while the disease progresses slowly, it can eventually lead to severe disability.

3. Potential Disorders Linked to CMAS:

While disorders directly linked to CMAS mutations are less commonly reported compared to GNE-related diseases, disruptions in CMAS activity could theoretically impair the activation of sialic acids, potentially leading to similar metabolic or immune dysfunctions. More research is needed to fully understand the clinical implications of CMAS-related defects.

Conclusion

Sialic acid biosynthesis is a fundamental biochemical pathway critical for maintaining proper cellular function, immune regulation, and pathogen defense. The intricate steps involved in producing and activating sialic acids underscore their biological importance. Disruptions in this pathway, whether due to genetic mutations or environmental factors, can lead to a range of metabolic and neuromuscular disorders.

As our understanding of sialic acid metabolism grows, so too does the potential for developing targeted therapies for related disorders. Continued research into enzymes like GNE and CMAS will be essential for uncovering new insights into human health and disease.

Reference: Sialylation as an Important Regulator of Antibody Function
https://pmc.ncbi.nlm.nih.gov/articles/PMC9021442/

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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