Carbohydrates

Carbohydrates are neutral compounds composed of carbon, hydrogen, and oxygen that serve as the primary sources of energy in the human body. They can be divided into simple carbohydrates, which include monosaccharides (e.g., glucose, fructose, galactose) and disaccharides (e.g., sucrose, lactose), and complex carbohydrates, which include starch polysaccharides (e.g., starch, glycogen) and nonstarch polysaccharides (e.g., glucan, cellulose). Monosaccharides are directly absorbed by enterocytes. Disaccharides and polysaccharides require degradation into monosaccharides to be absorbed by hydrolytic enzymes, which are secreted by the salivary glands in the mouth (salivary amylase), intestinal villi (maltase, lactase), and pancreas (pancreatic amylase). Conditions that decrease the secretion of these enzymes result in malabsorption and maldigestion. Glucose and galactose are absorbed via sodium-glucose linked transporters (SGLTs) in the intestinal epithelial cells and translocated into the circulation via glucose transporter 2 (GLUT2). Fructose is absorbed into enterocytes via glucose transporter 5 (GLUT5) through facilitated diffusion. The uptake of glucose into other cells is mediated by glucose transporters 1 to 5. Intracellularly, monosaccharides are further metabolized by a series of enzymatic reactions that release ATP.

For details on the carbohydrate glucose, see “Glycolysis and gluconeogenesis” and “Glycogen metabolism.”

• Carbohydrates
  • Compounds consisting of carbon, oxygen, and hydrogen
  • Classified as simple (e.g., glucose, fructose, sucrose) or complex sugars (e.g., starch)
• Monosaccharide: a simple carbohydrate that cannot be further broken down by simple hydrolysis (e.g., glucose, fructose, galactose)
• Disaccharide: two monosaccharides linked by a glycosidic bond (e.g., sucrose, maltose, or lactose)
• Polysaccharide: multiple monosaccharides bound by glycosidic bonds (e.g., glycogen, cellulose, starch, peptidoglycans, glycosaminoglycans)
• Glycosidic bond: linkage between a carbohydrate and another molecule (e.g., carbohydrate and alcohol)
  • Two forms:
    • 1,4-α-glycosidic bond (OH group below the plane of the ring), e.g., maltose
    • 1,4-β-glycosidic bonds (OH above the plane of the ring), e.g., lactose, cellulose

Lactase is the only enzyme in the human body that can cleave β-glycosidic bonds, but it only cleaves those of the disaccharide lactose. There are no enzymes in the digestive tract that can cleave the β-glycosidic bonds of polysaccharides. Cellulose (fiber) therefore remains undigested in the intestine.

Carbohydrates (also known as saccharides) are often represented by the general formula C_n(H₂O)_n. Chemically, they are polyhydroxy aldehydes or polyhydroxy ketones, meaning they possess one carbonyl group and at least two hydroxyl groups.

Monosaccharides

Monosaccharides are the basic building blocks (monomers) of carbohydrates.

Structure

• Basic structure: sugars with at least three carbon atoms, one carbonyl group, and at least two hydroxyl groups
  • Pentose: sugar with 5 carbon atoms, e.g., ribose and ribulose
  • Hexose: sugar with 6 carbon atoms, e.g., glucose and fructose
  • Aldose: carbonyl group of the sugar is an aldehyde (double bond at the terminal C-atom)
  • Ketose: carbonyl group of the sugar is a ketone (double bond at a secondary C-atom)
• Ring formation: In solution, and therefore also in the human body, monosaccharides exist predominantly in their ring form rather than as open-chain structures
  • Pyranose: a six-membered ring (e.g., glucose)
  • Furanose: a five-membered ring (e.g., fructose)
  • Aldose ring formation
    • The aldehyde group reacts with a hydroxyl group to form an intramolecular hemiacetal.
    • For glucose, this occurs when the aldehyde at the C1 atom reacts with the hydroxyl at the C5 atom, resulting in pyranose.
  • Ketose ring formation
    • The keto group reacts with a hydroxyl group to form an intramolecular hemiketal.
    • In fructose, the keto group at the C2 atom typically reacts with the hydroxyl at either the C5 (forming a furanose) or the C6 (forming a pyranose).
• Stereoisomerism: Carbohydrates exist in a large number of isomeric forms.
  • Anomers
    • Ring formation creates a new chirality (asymmetric center) at the former carbonyl carbon, known as the anomeric center .
    • α-form: hydroxyl group is below the ring plane (Haworth projection)
    • β-form: hydroxyl group is above the ring plane (Haworth projection)
    • Mutarotation: In an aqueous environment, the α- and β-forms interconvert through an open-chain intermediate until equilibrium is reached, affecting the optical rotation.
  • Enantiomers: non-superimposable mirror images (e.g., D-glucose vs. L-glucose); for a carbohydrate, this means all OH groups on asymmetric C-atoms have the opposite configuration.
    • D-form: hydroxyl group on the asymmetric carbon farthest from the carbonyl points right (in the Fischer projection)
    • L-form: hydroxyl group points left (in the Fischer projection)
    • Example: D-glucose and L-glucose
  • Diastereomers: stereoisomers that are not mirror images (e.g., L-glucose and D-galactose)
  • Epimers: specific type of diastereomer that differs at one chiral center (e.g., D-glucose and D-galactose)

D-Glucose can be identified in the Fischer projection by the specific arrangement of its OH groups (on C2, C3, C4, and C5): "right-left-right-right" (read from top to bottom)!

Classification

• By number of C-atoms: trioses (3), tetroses (4), pentoses (5), hexoses (6), heptoses (7)
• By position of the carbonyl group
  • Aldoses: carbonyl group is positioned at the terminal end of the molecule
  • Ketoses: carbonyl group is located within the carbon chain
• Combined: e.g., aldohexose (a monosaccharide with 6 C-atoms and a terminal carbonyl group)
• By ring size: e.g., pyranoses (six-membered ring), furanoses (five-membered ring)

Representation

Carbohydrates can be depicted in several structural forms:

• Fischer projection: open-chain structure
  • Carbon atoms are arranged vertically from top to bottom, with substituents (hydrogens and hydroxyl groups) drawn to the right or left of the carbon chain.
• Haworth projection: cyclic structure
  • The ring is represented in a plane, viewed from an angle. Substituents are depicted pointing either up or down from the ring.
• Conformational projection: chair and boat forms
  • These are three-dimensional representations of the ring structure, illustrating additional angles.
  • The chair form is more stable than the boat form and better represents the spatial arrangement of monosaccharides.

F-L-O-H: Substituents on the left in the Fischer projection are over (above) in the Haworth projection!

Reactions

Monosaccharides are very reactive. The following table provides an overview of possible reactions and their products using glucose as an example:

Reaction	Product	Structural formula
Oxidation of the C1-atom	Gluconolactone
Oxidation of the terminal CH2OH group	Glucuronic acid
Reduction of the C1 carbonyl group	Sorbitol (sugar alcohol)
Substitution of a hydroxyl group with an amino group Acetylation of the amino group	Glucosamine (amino sugar) N-Acetylglucosamine

Glucuronic acid plays an important role in biotransformation. It is primarily attached to steroids, bilirubin, and phenol rings, making them water-soluble and excretable!

The glycosidic bond

Monosaccharide units are connected by glycosidic bonds, which are crucial for forming larger carbohydrates. This bond is established through a reaction between the hemiacetal hydroxyl group at the anomeric carbon atom and another hydroxyl or amino group. During this process, a water molecule is eliminated, classifying it as a condensation reaction. The result of this reaction is the formation of an acetal.

Disaccharides

• Definition: two monosaccharides linked by an O-glycosidic bond
• Types
  • Reducing disaccharides: The glycosidic bond is established between the hydroxyl group of an anomeric carbon atom and a non-anomeric carbon atom.
    • Result: One anomeric carbon remains free, allowing the disaccharide to be further oxidized.
  • Non-reducing disaccharides: The glycosidic bond forms between the hydroxyl groups of two anomeric carbon atoms.
    • Result: Both anomeric carbons are bonded, leaving no free anomeric carbon available for oxidation.

Overview of the most important disaccharides
Name	Structural formula	Molecules	Bond type
Sucrose (“Table sugar”)		1× Glucose 1× Fructose	α-Glc-(1,2)-β-Fru: The hydroxyl group at the α-configured, anomeric C1-atom of glucose connects with the hydroxyl group at the β-configured, anomeric C2-atom of fructose (non-reducing disaccharide)
Maltose		2× Glucose	α-Glc-(1,4)-Glc: The hydroxyl group at the α-configured, anomeric C1-atom of one glucose molecule forms a bond with the hydroxyl group at the C4-atom of the second glucose molecule (reducing disaccharide)
Lactose (“Milk sugar”)		1× Glucose 1× Galactose	β-Gal-(1,4)-Glc: The hydroxyl group at the β-configured, anomeric C1-atom of galactose connects with the hydroxyl group at the C4-atom of the α- or β-configured glucose (reducing disaccharide)

Oligosaccharides

• Definition: three to ten glycosidically linked monosaccharides (linearly or in a branched manner)
• Occurrence in the organism
  • Commonly found in plant-based foods
  • Often attach to lipids or membrane-bound proteins, forming glycolipids and glycoproteins
  • Play a crucial role in cell surface recognition and differentiation, such as determining blood group types in the ABO system

Polysaccharides

• Definition: polymers of more than ten O-glycosidically linked monosaccharides
  • Homoglycans: made up of identical monosaccharide units
  • Heteroglycans: composed of different monosaccharide units and frequently linked to proteins, peptides, or lipids

Important homoglycans made from the basic building block glucose

Name		Structural formula	Bond type	Function in the organism
“Starch” (consists of about 70% amylopectin and about 30% amylose)			Amylopectin: α-1,4- and α-1,6-glycosidic Amylose: α-1,4-glycosidic	Most important dietary carbohydrate
Glycogen			α-1,4- and α-1,6-glycosidic	Storage form of carbohydrates in the human organism
Cellulose			β-1,4-glycosidic	Component of plant cell walls

The human digestive tract has no enzymes that can cleave the β-1,4-glycosidic bonds found in cellulose. Cellulose therefore remains undigested in the intestine and is referred to as dietary fiber!

Important heteroglycans

• Glycoproteins
  • Definition: proteins that have oligosaccharide chains (glycans) attached
    • A frequently occurring carbohydrate in glycoproteins is N-acetylglucosamine, which is linked to asparagine residues through a process known as N-glycosylation.
  • Functions: serve critical roles as membrane proteins, plasma proteins, and mucins
    • In mucins, the carbohydrate chains are typically attached to serine and threonine residues in the protein.
• Proteoglycans
  • Definition: proteins that contain multiple covalently linked glycosaminoglycan (GAG) side chains, which are negatively charged due to the presence of sulfate groups
  • Function: important component of the extracellular matrix
  • Composition of glycosaminoglycans: linear polysaccharides made up of repeating disaccharide units, typically consisting of a uronic acid (often glucuronic acid) and an amino sugar (usually N-acetylglucosamine)
    • Example GAGs:
      • Heparin (anticoagulant drug)
      • Chondroitin sulfate (found, e.g., in cartilage)
      • Hyaluronic acid (important component of the skin and synovial fluid)
• Peptidoglycans
  • Definition: composed of long carbohydrate chains linked by short peptide chains
  • Function: essential components of the bacterial cell wall, specifically murein

Carbohydrates in food

• Sources: table sugar, cereals, fruits, and vegetables
  • Approx. ⅔ of carbohydrates in food are in the form of starch (polysaccharide).
  • Approx. ⅓ of carbohydrates in food are in the form of disaccharides (e.g., lactose, sucrose).

Digestion

• Monosaccharides: absorbed directly by enterocytes
• Polysaccharides: broken down by enzymes into monosaccharides via hydrolytic cleavage of α-glycosidic bonds

• Lactase production decreases after breastfeeding, which leads to many individuals developing lactose intolerance. ^[1]

Absorption of glucose

Glucose enters intestinal epithelial cells and proximal renal tubular cells via SGLT. In all other cells of the body, glucose uptake occurs via specific membranous glucose transporters (e.g., GLUT2, GLUT5).

• Transporters
  • Sodium-dependent glucose cotransporter 1 (SGLT1): a specific transporter, located on the luminal side of mucosa cells and the proximal straight tubule in the kidney
  • Glucose transporters (GLUTs): a group of specific glucose transporters that are present in the plasma membranes of almost all cells of the body
• Intestinal glucose absorption: via SGLT1
  • Secondary active transport: The driving force of absorption is a sodium concentration gradient maintained by basal Na⁺/K⁺ ATPase, which transports sodium out of the cell.
  • Sodium moves down its concentration gradient into the cell, taking a glucose molecule with it each time.
• Transport into the blood: via GLUT2 (circulates unbound in the blood)
• Glucose uptake into cells: passive transport via facilitated diffusion
• Renal glucose reabsorption
  • Free filtration of glucose by the kidneys
  • Complete reabsorption (urine normally is glucose-free) in the proximal tubules via two types of SGLT
    • A membrane protein that mediates glucose and sodium transport across apical cell membranes in the small intestine and kidneys.
    • Utilizes the energy provided by the sodium gradient across the cell membrane for active glucose transport.
    • SGLT1
      • Reabsorbs the remaining glucose (∼ 2%) as well as galactose in the PCT
      • One molecule of glucose is absorbed together with two molecules of sodium
    • SGLT2
      • Reabsorbs ∼ 98% of urinary glucose in the proximal convoluted tubule (PCT)
      • One molecule of glucose is absorbed together with one molecule of sodium.
  • Reabsorption also relies on a sodium concentration gradient via Na⁺/K⁺ ATPase.

“Only GLUT4 has a need 4 insulin.”

BRICK LIPS: Brain, RBCs, Intestine, Cornea, Kidney, Liver, Islet cells, Placenta, Spermatocytes (insulin-independent glucose uptake)

Specific insulin-independent glucose transporters: GLUT1 and GLUT3 for BBB (blood-brain barrier); GLUT2 transports in both directions; GLUT5 (five) is a fructose transporter.

Metabolism of glucose

• See “Breakdown and synthesis of glucose“ for:
  • Glucose degradation
    • Glycolysis
    • Hexose monophosphate shunt (pentose phosphate pathway)
  • Glucose synthesis: See “Gluconeogenesis.”
• See “Glycogen metabolism“ for glucose storage.
• See “Sources of ATP synthesis” for ATP synthesis pathways and caloric values.

Absorption of galactose

Galactose is part of lactose (found in milk products).

1. Lactose is cleaved in the small intestine by lactase.
2. Free galactose is absorbed by enterocytes via SGLT1.
3. Free galactose is transported into blood via GLUT2.
4. Galactose circulates to the liver for further metabolism.

Breakdown of galactose

1. Galactokinase activates galactose: galactose + ATP → galactose-1-P + ADP
2. Galactose-1-phosphate uridyltransferase: galactose-1-P + UDP-glucose → UDP-galactose + glucose-1-P (can be fed into glycolysis)
3. UDP-galactose 4-epimerase: UDP-galactose → UDP-glucose

If an individual is deficient in the enzyme galactose-1-phosphate uridyltransferase (classical galactosemia), galactose and lactose (galactose + glucose) have to be removed from their diet.

High blood levels of galactose also result in conversion to the osmotically active galactitol via aldose reductase. In individuals with galactokinase deficiency, excess galactitol forms in the lens of the eye and leads to early-onset cataracts.

Galactose synthesis

• Metabolic site: lactating breast (lactose is the main sugar of breast milk)
• Reversal of all breakdown reactions

Absorption of fructose

1. Sucrose is cleaved in the small intestine by sucrase-isomaltase.
2. Freed fructose is absorbed into enterocytes via facilitated diffusion by GLUT5.
3. Freed fructose is transported into the blood via GLUT2.
4. Fructose circulates to the liver for further metabolism.

Breakdown of fructose (fructolysis)

1. Fructokinase activates fructose: fructose + ATP → fructose-1-P + ADP
2. Aldolase B splits hexose into two trioses: fructose-1-P → dihydroxyacetone-P + glyceraldehyde
3. Trioses are converted to glyceraldehyde-3-P:
   • Triosephosphate isomerase: dihydroxyacetone-P (can directly enter glycolysis) → glyceraldehyde-3-P
   • Triose kinase: glyceraldehyde + ATP → glyceraldehyde-3-P
4. Glyceraldehyde-3-P is fed into glycolysis.

If an individual is deficient in the enzyme aldolase B (e.g., due to hereditary fructose intolerance), both fructose and sucrose (fructose + glucose) have to be removed from the diet.

Fructose synthesis

• Fructose can be produced from glucose via sorbitol (osmotically active sugar alcohol) without using ATP.
• In the body, fructose is the primary source of energy for spermatozoa.
• Enzymes
  • Aldose reductase
    • Reduces glucose to sorbitol: glucose + NADPH → sorbitol
    • Can convert galactose to galactitol (a sugar alcohol) when galactose levels in blood are high
  • Sorbitol dehydrogenase oxidates sorbitol to fructose: sorbitol + NAD⁺ → fructose
• Tissues that have both aldose reductase and sorbitol dehydrogenase (liver, ovaries, seminal vesicles) will not accumulate sorbitol.
• Tissues/cells that do not have sorbitol dehydrogenase activity (e.g., lens, retina, kidneys, Schwann cells) accumulate sorbitol.
• Excess sorbitol causes osmotic damage and explains changes seen in hyperglycemic diabetic patients such as diabetic cataracts, diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

No LOVE for sorbitol in the Liver, Ovaries, and seminal VEsicles.

• Maldigestion and malabsorption
  • Lactose intolerance
  • Fructose intolerance
  • Sucrose malabsorption (sucrase-isomaltase deficiency)
  • Sorbitol malabsorption
• Disorders of glucose metabolism
  • Diabetes mellitus type 1, diabetes mellitus type 2
  • Glycogen storage disorders (GSD)
• Disorders of galactose metabolism: galactosemia
• Disorders of fructose metabolism
  • Hereditary fructose intolerance (autosomal recessive defect of aldolase B)
  • Essential fructosuria (autosomal recessive defect of fructokinase)