H OH metabolites OH Review Fructose and Mannose in Inborn Errors of Metabolism and Cancer Elizabeth L. Lieu †, Neil Kelekar †, Pratibha Bhalla † and Jiyeon Kim * Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL 60607, USA; [email protected] (E.L.L.); [email protected] (N.K.); [email protected] (P.B.) * Correspondence: [email protected] † These authors contributed equally to this work. 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. Keywords: fructose and mannose; inborn errors of metabolism; cancer Citation: Lieu, E.L.; Kelekar, N.; Bhalla, P.; Kim, J. Fructose and Mannose in Inborn Errors of Metabolism and Cancer. Metabolites 1. Introduction 2021, 11, 479. https://doi.org/ The cultivation of grains to create a reliable source of carbohydrates was a crucial step 10.3390/metabo11080479 in the cultural transition from nomadism to sedentism. Humans have evolved enhanced utilization of glucose as the central carbon source that feeds into catabolic and anabolic Academic Editor: Victor Gault pathways, including the long-term storage of glucose as glycogen. Glucose, the major dietary monosaccharide with six carbon atoms (hexose), is an essential part of a healthy diet, Received: 26 June 2021 and as such, a great emphasis has been placed on the study of glucose metabolism. Through Accepted: 21 July 2021 Published: 25 July 2021 a diversity of mechanisms and interactions, dysregulations of glucose metabolism—namely, perturbations in central carbon metabolism (glycolysis, pentose phosphate pathway (PPP), Publisher’s Note: MDPI stays neutral and tricarboxylic acid (TCA) cycle)—are recognized as key steps not only in metabolic with regard to jurisdictional claims in disorders (e.g., obesity, insulin intolerance, nonalcoholic fatty liver disease) but also in published maps and institutional affil- cancer progression [1–3]. However, glucose is not the only hexose metabolized by the iations. cell; fructose and mannose encompass two important hexoses that cells use for energy production [4] and intricate cellular processes, such as glycosylation [5]. While fructose and mannose are not essential to the human diet, the prevalent role of metabolism in disease has shifted the field to place an increased importance on the study of these two non-essential hexoses in recent years. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Consumed in lower amounts as recently as a century ago, fructose, oftentimes called This article is an open access article fruit sugar, has been extensively studied since its discovery by Augustin-Pierre Dubrunfaut distributed under the terms and in 1847 and the elucidation of its configuration by Emil Fischer’s stereochemistry study conditions of the Creative Commons in the late 1800s. Fructose has become increasingly present in the Western pattern diet Attribution (CC BY) license (https:// through the increased availability of sucrose and high-fructose corn syrup. As fructose creativecommons.org/licenses/by/ has transitioned to a stalwart part of the average diet in the forms of processed breads and 4.0/). colas, fructose has been shown to play a chronologically and statistically significant role in Metabolites 2021, 11, 479. https://doi.org/10.3390/metabo11080479 https://www.mdpi.com/journal/metabolites Metabolites 2021, 11, 479 2 of 23 Metabolites 2021, 11, x FOR PEER REVIEW 2 of 23 the increased prevalence of obesity and metabolic syndrome, particularly in the United Statesand [colas,6,7]. fructose Given thathas been the diagnosticshown to play criteria a chronologically for metabolic and statistically syndrome significant include central role in the increased prevalence of obesity and metabolic syndrome, particularly in the obesity, hyperglycemia, dyslipidemia, and hypertension, fructose’s relationship with the United States [6,7]. Given that the diagnostic criteria for metabolic syndrome include cen- developmenttral obesity, ofhyperglycemia, high morbidity dyslipidemia, conditions and emphasizes hypertension, the fructose’s importance relationship of studying with and understandingthe development fructose of high metabolism morbidity conditions as it relates emphasizes to disease the development importance of and studying progression. Whileand enzymatic understanding function fructose in metabolism fructose metabolism as it relates to can disease correspond development to poor and metabolic progres- prog- noses,sion. so While too canenzymatic enzymatic function deficiencies in fructose inmetabolism the pathway. can correspond To date, threeto poor inborn metabolic errors are knownprognoses, in the so pathway too can enzymatic of fructose deficiencies metabolism: in the pathway. fructokinase To date, deficiency, three inborn aldolase errors B defi- ciency,are known and fructose-1,6-bisphosphatase in the pathway of fructose metaboli deficiencysm: fructokinase (Figure1 ).deficiency, Together, aldolase these deficienciesB de- emphasizeficiency, theand importance fructose-1,6-bisphosphatase of fructose metabolism deficiency through (Figure 1). anabolic Together, and these catabolic deficien- processes: thecies trapping emphasize of fructose the importance in the cell,of fructose the contribution metabolism through of fructose anabolic to metabolic and catabolic intermediates, pro- cesses: the trapping of fructose in the cell, the contribution of fructose to metabolic inter- and the roles of fructose in glycogenesis. mediates, and the roles of fructose in glycogenesis. Figure 1.FigureFructose 1. Fructose and mannose and mannose inborn inborn errors errors of metabolic of metabolic disease. diseas Ae. A number number of of inborn inborn errors errors areare relatedrelated to perturbed perturbed sugar sugar metabolism, including fructose and mannose. Fructose and mannose transport occurs through glucose transporters metabolism,due to including their similarity fructose in structure. and mannose. Essential Fructose fructosuria and and mannose hereditary transport fructose intolerance occurs through affect fructolysis glucose transporters through de- due to their similarityficiency in in KHK structure. and ALDOB, Essential respectively. fructosuria These and pathways hereditary feed into fructose the glycolysis intolerance pathways affect through fructolysis GA to through G3P conver- deficiency in KHKsion and and ALDOB, DHAP production. respectively. FBPase These deficiency pathways affects feed fructose into metabolism the glycolysis by loss pathways of FBP1 activity through blocking GA gluconeogen- to G3P conversion esis. Mannose metabolism, which is linked to fructose metabolism by the enzyme MPI, is also subject to mutations causing and DHAP production. FBPase deficiency affects fructose metabolism by loss of FBP1 activity blocking gluconeogenesis. inborn errors. The central role of mannose in glycosylation explains the inborn errors classified as congenital disorders of Mannoseglycosylation. metabolism, MPI-CDG, which PMM2-CDG, is linked to and fructose ALG11-CDG metabolism relate to by the the deficiency enzyme of MPI, the enzyme is also listed subject in their to mutations names caus- causing inborn errors.ing hypoglycosylation. The central role These of mannosechanges affect in glycosylation proper protein explains folding, leading the inborn to aberrant errors cellular classified function. as congenital Types of inborn disorders of glycosylation.errors of MPI-CDG, metabolism PMM2-CDG,are shown in light and green ALG11-CDG boxes. Protei relatens: GLUT, to the Glucose deficiency transporter; of the enzyme KHK, Ketohexokinase; listed in their ALDOB, names causing 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. Types of inborn ALG11: GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase; Metabolites: GA; Glyceraldehyde; DHAP: errors ofDihydroxyacetone metabolism are phosphate; shown in lightFructose-1P: green boxes.Fructose-1-phosp Proteins:hate; GLUT, Glucose-6P: Glucose transporter;Glucose-6-phosphate; KHK, Ketohexokinase; Fructose-6P: Fruc- ALDOB, Aldolase B; FBP1: Fructose-1,6-bisphosphatase 1; MPI: Mannose phosphate isomerase; PMM2: Phosphomannomutase 2; ALG11: GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase; Metabolites: GA; Glyceraldehyde; DHAP: Dihydroxyacetone phosphate; Fructose-1P: Fructose-1-phosphate;