Abstract
History suggests that tasteful properties of sugar have been domesticated as far back as 8000 BCE. With origins in New Guinea, the cultivation of sugar quickly spread over centuries of conquest and trade. The product, which quickly integrated into common foods and onto kitchen tables, is sucrose, which is made up of glucose and fructose dimers. While sugar is commonly associated with flavor, there is a myriad of biochemical properties that explain how sugars as biological molecules function in physiological contexts. Substantial research and reviews have been done on the role of glucose in disease. This review aims to describe the role of its isomers, fructose and mannose, in the context of inborn errors of metabolism and other metabolic diseases, such as cancer. While structurally similar, fructose and mannose give rise to very differing biochemical properties and understanding these differences will guide the development of more effective therapies for metabolic disease. We will discuss pathophysiology linked to perturbations in fructose and mannose metabolism, diagnostic tools, and treatment options of the diseases.
Highlights
Many studies on metabolic diseases focus on glucose, there are substantial ailments that arise due to perturbations in mannose and fructose metabolism pathways
Research on these overlooked monosaccharides has increased over the past decade to shine new light on fructose and mannose metabolism
Substantial progress has been made in understanding the biological mechanisms, physiological, and health consequences of defective fructose and mannose metabolism
Summary
The cultivation of grains to create a reliable source of carbohydrates was a crucial step in the cultural transition from nomadism to sedentism. Aldolase B; FBP1: Fructose-1,6-bisphosphatase 1; MPI: Mannose phosphate isomerase; PMM2: Phosphomannomutase 2; hypoglycosylation These changes affect proper protein folding, leading to aberrant cellular function. Proteins: GLUT, Glucose transporter; ALDOB, Fructose-1P: Fructose-1-phosphate; Glucose-6P: Glucose-6-phosphate; Fructose-6P: FrucAldolase B; FBP1: Fructose-1,6-bisphosphatase 1; MPI: Mannose phosphate isomerase; PMM2: Phosphomannomutase 2; Dihydroxyacetone phosphate; Fructose-1P: Fructose-1-phosphate; Glucose-6P: Glucose-6-phosphate; Fructose-6P: Fructose6-phosphate; Fructose-1,6BP: Fructose-1,6-bisphosphate; Mannose-6P: Mannose-6-phosphate; Mannose-1P: Mannose1-phosphate; GDP-mannose: Guanosine diphosphate mannose; G3P, Glyceraldehyde-3-phosphate; Pathways: TCA, tricarboxylic acid; Disease: CDG: Congenital disorders of glycosylation. Inborn errors of mannose metabolism discussed in the review are congenital disorders of glycosylation (CDGs) caused by loss of function of three enzymes in the mannose metabolism pathway: mannose phosphate isomerase (MPI, MPI-CDG), phosphomannomutase 2 (PMM2, PMM2-CDG), and ALG11 alpha-1,2mannosyltransferase (ALG11, ALG11-CDG) (Figure 1). The review will explore the link between dysfunction of fructose and mannose metabolism and other metabolic disorders, such as cancers
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