N-Acetylmannosamine, commonly known as ManNAc, is a naturally occurring hexosamine monosaccharide, a type of simple sugar found in the human body. It is a stable compound and plays a role in various cellular functions.
How ManNAc Works in Your Body
ManNAc serves as a precursor for the biosynthesis of sialic acids. Sialic acids are negatively charged sugar molecules found on the surface of nearly all cells, attached to proteins and lipids. These molecules are crucial for numerous cellular processes.
The creation of sialic acids begins in the cytoplasm of cells, where UDP-GlcNAc, a molecule derived from glucose, is converted into ManNAc. This conversion is a rate-limiting step in the sialic acid biosynthesis pathway, meaning it controls the overall speed of sialic acid production. The enzyme UDP-GlcNAc 2-epimerase, encoded by the GNE gene, facilitates this initial transformation.
Following its formation, ManNAc is then phosphorylated by ManNAc kinase, also encoded by the GNE gene, to become ManNAc-6-phosphate. This intermediate is further processed into N-acetylneuraminic acid (Neu5Ac), the most common form of sialic acid in human tissues. Neu5Ac is then activated by CMP-sialic acid synthetase in the nucleus, forming CMP-sialic acid.
CMP-sialic acid acts as a donor molecule, adding sialic acids to nascent glycoproteins and glycolipids in the Golgi apparatus. These sialylated glycoconjugates are involved in diverse cellular functions, including cell-to-cell communication and immune system recognition. Sialic acids also contribute to stabilizing proteins and maintaining the structural integrity of cell membranes.
When ManNAc Goes Wrong
Disruptions in the ManNAc pathway or sialic acid production can lead to several health problems. A notable condition linked to these issues is GNE myopathy. This rare, progressive muscle-wasting disease is caused by mutations in the GNE gene.
A deficiency in the GNE enzyme’s activity results in reduced sialic acid synthesis, leading to hyposialylation of muscle proteins and glycosphingolipids. This deficiency manifests as progressive muscle weakness and atrophy, typically starting in the distal muscles of the lower limbs. Patients often experience symptoms like foot drop and can become wheelchair-bound.
Beyond GNE myopathy, altered sialic acid levels can also be involved in certain kidney diseases. Sialylated glycoconjugates are important components of the glomerular glycocalyx, a layer in the kidney’s filtering units that helps regulate what passes into the urine. Insufficient sialic acid in the glomerulus can lead to conditions like severe glomerular proteinuria, where excess protein leaks into the urine, and may affect overall kidney health. Some patients with specific glomerular diseases have demonstrated kidney sialic acid insufficiency on their glomerular proteins.
ManNAc as a Potential Treatment
ManNAc supplementation is being explored as a therapeutic strategy, particularly for conditions like GNE myopathy. Providing an external source of ManNAc can help bypass the impaired GNE enzyme activity and increase the body’s production of sialic acid. This increased sialic acid availability could potentially alleviate symptoms or slow the progression of the disease.
Clinical trials have investigated the safety and efficacy of ManNAc in individuals with GNE myopathy. Early phase studies have indicated that oral administration of ManNAc is generally well-tolerated and can lead to a sustained increase in plasma free sialic acid levels. A phase 2 clinical trial involving patients with GNE myopathy showed an increase in sialic acid in the blood and sialylation in muscle cell membranes after three months of treatment. This trial also observed a slowing of the decline in muscle strength in both upper and lower limbs and a decrease in disease progression.
Research is ongoing, with multi-center, randomized, placebo-controlled, double-blind trials planned or underway to further evaluate ManNAc’s long-term safety and clinical effectiveness in GNE myopathy. ManNAc is also being investigated for its potential in treating other conditions where sialic acid deficiency plays a role, including certain primary glomerular diseases that involve issues with the kidney’s filtration barrier. Studies have shown that ManNAc supplementation can partially reverse glomerular pathology and reduce proteinuria in various models of glomerular disease.