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Disorders of Monosaccharide Synthesis and Interconversion

Pathogenic mutations in glycosylation-related genes interfere with cellular glycosylation, resulting in abnormalities in many organs. Congenital Disorders of Glycosylation (CDG) are a rapidly expanding group of more than 135 rare metabolic diseases.

Providing energy to cells is the most important role of monosaccharides. In addition to energy-producing catabolism, they are used in the biosynthesis of various cellular components. In mammalian cells, the enzymatic hydrolysis of biosynthesis involves at least nine monosaccharides (glucose, galactose, N-acetylglucosamine, N-acetylgalactosamine, xylose, glucuronic acid, sialic acid, mannose, and caramel), which are linked to proteins and lipids to create hundreds of glycosyl structures.

Glycosylation is important for the biosynthesis, folding, stabilization, transport, and turnover of many different macromolecules, all of which play important roles in cell-cell interactions, tissue morphogenesis, and immune responses. Sugar metabolism is necessary for the generation of nucleotide sugars and dolichol-linked sugars for Golgi glycosylation reactions. Genetic disorders of glucose metabolism will affect multiple pathways.

Fig.1 Biosynthesis and interconversion of monosaccharides. (Sosicka, et al., 2019)

• L-Fucose Synthesis and Interconversion

L-fucose was incorporated into N- and O-glycans as well as glycolipids by using GDP-fucose as a donor substrate. GDP-fucose can also be synthesized de novo from glucose or mannose. In this process, GDP-mannose is converted to GDP-fucose in a three-step reaction by two enzymes, GDP-mannose 4,6-dehydratase (GMDS) and GDP-fucose synthase (TSTA3). catalytic. Alternatively, GDP-fucose can be synthesized directly from fucose via the dietary route. Fucose is first phosphorylated to fucose 1-phosphate (Fuc-1P) by fucose kinase (FCSK) and then further converted to GDP-fucose by guanylyltransferase (FPGT).

Little is known about fucose transport in human cells. More than two decades ago, it was shown to be a Na+-independent mechanism that occurs via an unknown carrier system. Once transported into cells, fucose is rapidly incorporated into glycoproteins, and a significant fraction of these glycoproteins are rapidly secreted. Incorporation requires the delivery of GDP-fucose into the Golgi and endoplasmic reticulum lumen. In humans, this transport process is mediated by SLC35C1 or SLC35C2.

At present, several genetic disorders of fucosylation are known, including a pathological variant of SLC35C1 that causes leukocyte adhesion deficiency II, also known as SLC35C1-CDG. In these individuals, fucosylation is disturbed due to malfunction of SLC35C1 resulting in immunodeficiency and severe intellectual and growth retardation, as well as its hallmark feature, elevated levels of circulating leukocytes.

• D-Galactose Synthesis and Interconversion

Galactosemia refers to mutations in three genes involved in Gal metabolism. Gal-1-P uridyltransferase (GALT) is defective in common galactosemia. This results in excess Gal-1-P, reducing the synthesis and effectiveness of UDP-Gal. UDP-Gal-4'- epimerase (GALE) or galactokinase (GALK) can also cause the disease, but they are less common.

Babies with GALT deficiency are stunted and have liver enlargement, jaundice, and cataracts. A lactose-free diet improves most acute symptoms by reducing the amount of Gal entering the pathway and the accumulation of Gal and Gal-1-P. Reducing Gal reduces the production of galactitol and galactonic acid through the reductive and oxidative metabolism of Gal, respectively. A sugar-free diet apparently does not prevent the cognitive impairment, ataxia, growth retardation, and ovarian dysfunction characteristic of this disease. Aberrant glycosylation of glycoproteins and glycolipids is observed in some GALT-deficient individuals. However, this is not directly related to galactose deficiency. In the absence of GALT, a GALT-free diet normalizes glycation. However, dietary Gal supplementation was found to be an effective treatment for some symptoms of another CDG, PGM1-CDG. In PGM1-CDG, phosphoglucomutase activity leads to a decrease in UDP-Gal and UDP-Glc, resulting in galactosylation and loss of N-glycans. These biochemical abnormalities are restored by Gal's feeding. Hypoglycemia, abnormal liver and coagulation function, and gonadal hormone levels improved after clinical treatment.

Here we describe one of the disorders in the Disorders of Multiple Glycosylation and Other Pathways. CD BioGlyco provides a range of Monosaccharide products to customers. We also provide high-quality Monosaccharides-based Glycomedicine Development, Quantitative Analysis of Monosaccharides, and Custom Monosaccharide Synthesis services to meet the individual needs of customers. If you are interested in our services, please contact us for more details without any hesitation.

Reference:

1. Sosicka, P.; et al. Therapeutic monosaccharides: looking back, moving forward. Biochemistry. 2019, 59(34): 3064-3077.