12. Carbohydrate Chemistry
Reading time: ~45 minutes | Key topics: Monosaccharide stereochemistry, cyclization and anomers, sugar derivatives, glycosidic bonds, polysaccharides, glycoconjugates
Introduction to Carbohydrates
Carbohydrates are the most abundant class of biomolecules on Earth. The name derives from their general empirical formula, which suggests "hydrates of carbon":
While this formula holds for many simple sugars (e.g., glucose: C6H12O6), it is not universal: some carbohydrates contain nitrogen, sulfur, or phosphorus, and some compounds fitting this formula (e.g., formaldehyde, CH2O, or acetic acid, C2H4O2) are not carbohydrates.
Classification by Size
- Monosaccharides: Single sugar units (glucose, fructose, galactose). Cannot be hydrolyzed further.
- Disaccharides: Two monosaccharides joined by a glycosidic bond (sucrose, lactose, maltose)
- Oligosaccharides: Short chains of 3-10 monosaccharides (found on glycoproteins and glycolipids)
- Polysaccharides: Long polymers of hundreds to thousands of monosaccharide units (starch, glycogen, cellulose)
Biological Functions
Monosaccharide Structure
Monosaccharides are polyhydroxy aldehydes (aldoses) or polyhydroxy ketones (ketoses). They are further classified by the number of carbon atoms in the chain:
| Carbon # | Name | Aldose Example | Ketose Example |
|---|---|---|---|
| 3 (C3) | Triose | D-Glyceraldehyde | Dihydroxyacetone |
| 4 (C4) | Tetrose | D-Erythrose | D-Erythrulose |
| 5 (C5) | Pentose | D-Ribose | D-Ribulose |
| 6 (C6) | Hexose | D-Glucose | D-Fructose |
Stereoisomers and Chirality
Most monosaccharides contain one or more chiral (asymmetric) carbon atoms. For a sugar with $n$ chiral centers, the number of possible stereoisomers is:
For D-glucose ($n = 4$ chiral centers): $2^4 = 16$ stereoisomers (8 D-aldohexoses and 8 L-aldohexoses). Fischer projections depict these stereoisomers with the carbon chain vertical and the most oxidized carbon at the top.
D and L Designations
The D/L system is based on the configuration at the highest-numbered chiral center (the chiral center farthest from the carbonyl). If the hydroxyl group on this carbon points to the right in the Fischer projection, the sugar is D; if it points to the left, it is L. Most naturally occurring sugars are in the D configuration.
Key Terminology
- Enantiomers: Mirror-image stereoisomers (D-glucose and L-glucose)
- Diastereomers: Stereoisomers that are not mirror images
- Epimers: Diastereomers differing at exactly one chiral center (D-glucose and D-galactose differ at C4; D-glucose and D-mannose differ at C2)
Cyclization and Anomers
In aqueous solution, monosaccharides with five or more carbons exist predominantly in cyclic forms. Cyclization occurs by intramolecular reaction between the carbonyl group and a hydroxyl group:
Hemiacetal Formation (Aldoses)
The aldehyde at C1 reacts with a hydroxyl group (usually C5 for hexoses) to form a hemiacetal, creating a six-membered pyranose ring (or with C4 to form a five-membered furanose ring).
Hemiketal Formation (Ketoses)
The ketone at C2 reacts with a hydroxyl group (usually C5 for hexoses) to form a hemiketal, creating a five-membered furanose ring (or with C6 to form a six-membered pyranose ring).
The Anomeric Carbon
Cyclization creates a new chiral center at the former carbonyl carbon, called the anomeric carbon (C1 in aldoses, C2 in ketoses). The two possible configurations are called anomers:
- α anomer: The hydroxyl on the anomeric carbon is axial (pointing down in Haworth projection for D-sugars; on the same side as the reference carbon)
- β anomer: The hydroxyl on the anomeric carbon is equatorial (pointing up in Haworth projection for D-sugars; on the opposite side from the reference carbon)
Mutarotation
When a pure anomer is dissolved in water, the optical rotation changes over time until reaching an equilibrium value. This is mutarotation — the interconversion between α and β anomers via the open-chain form:
At equilibrium, D-glucose in solution is approximately 36% α and 64% β (the β anomer is more stable because the C1 hydroxyl is equatorial, minimizing 1,3-diaxial interactions). Less than 0.003% exists in the open-chain form at any given time.
Sugar Derivatives
Many biologically important carbohydrates are chemically modified monosaccharides. These derivatives play critical roles in metabolism, structural biology, and cell signaling.
Sugar Acids
Oxidation of monosaccharides produces sugar acids. Gluconic acid: C1 aldehyde oxidized to carboxyl (product of glucose oxidase, used in blood glucose test strips). Glucuronic acid: C6 primary alcohol oxidized to carboxyl (used in Phase II drug metabolism in the liver for conjugation and excretion of hydrophobic compounds). Glucaric acid (saccharic acid): Both C1 and C6 oxidized.
Sugar Alcohols (Alditols)
Reduction of the carbonyl group produces sugar alcohols. Sorbitol (glucitol): Reduction product of glucose; accumulates in the lens in diabetic cataracts (aldose reductase pathway). Mannitol: Reduction product of mannose; used clinically as an osmotic diuretic. Xylitol: From xylose; used as a sweetener (anti-cariogenic, not metabolized by oral bacteria).
Deoxy Sugars
A hydroxyl group is replaced by hydrogen. 2-Deoxyribose: The sugar component of DNA (missing the 2′-OH of ribose, making DNA more resistant to alkaline hydrolysis). L-Fucose (6-deoxy-L-galactose): Found in glycoproteins and blood group determinants. L-Rhamnose (6-deoxy-L-mannose): Found in plant glycosides and bacterial polysaccharides.
Amino Sugars
A hydroxyl (usually at C2) is replaced by an amino group. Glucosamine: Component of glycosaminoglycans (GAGs). N-Acetylglucosamine (GlcNAc): Subunit of chitin; component of N-linked glycans and bacterial peptidoglycan. N-Acetylmuramic acid (MurNAc): GlcNAc with a lactyl ether at C3; unique to bacterial cell wall peptidoglycan (target of lysozyme). Sialic acid (Neu5Ac): A 9-carbon amino sugar acid; terminal residue on glycoproteins; critical for cell-cell recognition.
Phosphorylated Sugars
Esterification with phosphate is critical for metabolic activation. Glucose-6-phosphate: First intermediate of glycolysis (hexokinase product); trapped inside the cell by the negative charge. Fructose-1,6-bisphosphate: Key intermediate in glycolysis (phosphofructokinase-1 product). Ribose-5-phosphate: Intermediate of the pentose phosphate pathway; precursor for nucleotide biosynthesis.
Disaccharides
Disaccharides are formed when two monosaccharides are joined by a glycosidic bond, a covalent bond formed by a condensation reaction between the anomeric carbon of one sugar and a hydroxyl group of the other. The bond is named by its configuration (α or β) and the carbon numbers involved.
Reducing vs. Non-Reducing Sugars
A reducing sugar has a free anomeric carbon that can open to expose the aldehyde (or can tautomerize to an aldehyde in ketoses), allowing it to reduce oxidizing agents such as Cu2+ (Benedict's/Fehling's reagent) or Ag+ (Tollens' reagent). If the anomeric carbons of both residues participate in the glycosidic bond, no free anomeric carbon remains and the disaccharide is non-reducing.
Important Disaccharides
| Disaccharide | Components | Bond | Reducing? | Source |
|---|---|---|---|---|
| Maltose | Glc + Glc | α(1→4) | Yes | Starch hydrolysis |
| Cellobiose | Glc + Glc | β(1→4) | Yes | Cellulose hydrolysis |
| Lactose | Gal + Glc | β(1→4) | Yes | Milk |
| Sucrose | Glc + Fru | α(1→β2) | No | Table sugar (plants) |
| Trehalose | Glc + Glc | α(1→α1) | No | Insects, fungi, bacteria |
Hydrolysis of Sucrose
Sucrose is the most abundant disaccharide in nature, synthesized in plants for energy transport. It is non-reducing because the anomeric carbons of both glucose and fructose are involved in the glycosidic bond. Enzymatic hydrolysis by sucrase (invertase) yields an equimolar mixture of glucose and fructose called "invert sugar" (the sign of optical rotation inverts):
Clinical note: Lactose intolerance results from deficiency of lactase (β-galactosidase) in the intestinal brush border, preventing hydrolysis of lactose into galactose and glucose. Undigested lactose is fermented by colonic bacteria, producing gas and osmotically active products.
Polysaccharides
Polysaccharides (glycans) are polymers of monosaccharides linked by glycosidic bonds. They serve two major functions: energy storage and structural support. The properties of a polysaccharide depend on the identity of its monosaccharide units, the type of glycosidic linkage, and the degree of branching.
Storage Polysaccharides
Starch (Plants)
The principal energy storage polysaccharide in plants. Found abundantly in seeds, tubers, and roots. Composed of two components:
- Amylose (~20-30%): Unbranched chains of glucose linked by α(1→4) bonds. Adopts a left-handed helical structure. Forms blue-black complex with iodine (diagnostic starch test).
- Amylopectin (~70-80%): Branched chains with α(1→4) backbone and α(1→6) branch points every 24-30 residues. Forms red-violet complex with iodine.
Glycogen (Animals)
The principal energy storage polysaccharide in animals, stored primarily in liver (~10% by weight) and skeletal muscle (~1-2%). Structurally similar to amylopectin but more highly branched, with α(1→6) branch points every 8-12 residues. This extensive branching provides many non-reducing ends, allowing rapid mobilization of glucose by glycogen phosphorylase during energy demand. A single glycogen granule may contain up to ~55,000 glucose residues with a molecular weight of ~107 Da.
Structural Polysaccharides
Cellulose
The most abundant organic polymer on Earth (~1011 tons produced annually by photosynthesis). Linear chains of glucose linked by β(1→4) bonds. The β-linkage forces alternate glucose residues to flip 180°, creating extended, flat ribbons that form strong interchain hydrogen bonds. These aggregate into microfibrils (36 chains) with enormous tensile strength. Humans lack the enzyme cellulase (β-glucosidase) and therefore cannot digest cellulose; it passes through the gut as dietary fiber. Ruminants (cows) and termites digest cellulose with the help of symbiotic bacteria in their gut.
Chitin
The second most abundant biological polymer. Composed of N-acetylglucosamine (GlcNAc) residues linked by β(1→4) bonds. Structurally similar to cellulose but with acetylamino groups at C2 instead of hydroxyl groups. Forms the exoskeleton of arthropods (insects, crustaceans) and the cell walls of fungi.
Peptidoglycan (Murein)
The rigid structural component of bacterial cell walls. Composed of alternating N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) residues linked by β(1→4) bonds. Short peptide chains on NAM residues cross-link adjacent glycan strands, creating a mesh-like structure. Lysozyme (found in tears, saliva) cleaves the NAG-NAM bond. Penicillin inhibits the transpeptidase that forms peptide cross-links, preventing cell wall synthesis in growing bacteria.
Why α vs. β Linkages Matter
Both starch and cellulose are glucose polymers, but their properties are dramatically different because of the glycosidic linkage geometry. The α(1→4) links in starch produce a helical structure suitable for compact energy storage, easily hydrolyzed by α-amylase. The β(1→4) links in cellulose produce extended flat chains that form strong hydrogen-bonded sheets, ideal for structural support but resistant to hydrolysis by most organisms.
Glycoconjugates
Carbohydrates are frequently found covalently attached to proteins or lipids, forming glycoconjugates. These sugar chains (glycans) on cell surfaces play crucial roles in cell recognition, signaling, and protection.
Glycoproteins
Proteins with covalently attached oligosaccharide chains. Most extracellular and membrane proteins are glycoproteins. Two types of glycosylation:
- N-linked: Oligosaccharide attached to the amide nitrogen of Asn in the Asn-X-Ser/Thr sequon. Added in the ER as a 14-sugar precursor; trimmed and modified in the Golgi. Found on most secreted and membrane glycoproteins.
- O-linked: Sugars added individually to the hydroxyl oxygen of Ser or Thr. Occurs mainly in the Golgi. Prominent in mucins (heavy O-glycosylation creates a gel-like protective layer on epithelial surfaces).
Proteoglycans and Glycosaminoglycans (GAGs)
Proteoglycans consist of a core protein with one or more covalently attached glycosaminoglycans (GAGs) — long, unbranched polysaccharides of repeating disaccharide units, typically containing an amino sugar and a uronic acid:
Glycolipids
Lipids with covalently attached sugar chains, found in the outer leaflet of cell membranes. Cerebrosides: Ceramide + single sugar (galactose in brain, glucose in other tissues). Gangliosides: Ceramide + complex oligosaccharide containing sialic acid. Important in nerve cell membranes and cell-cell recognition. GM2 ganglioside accumulates in Tay-Sachs disease (hexosaminidase A deficiency).
Blood Group Antigens (ABO System)
The ABO blood group is determined by the terminal sugar residues on glycolipids and glycoproteins of red blood cell surfaces. All three types share a common core oligosaccharide (the H antigen). Type A: Adds N-acetylgalactosamine (GalNAc) to H antigen (N-acetylgalactosaminyltransferase). Type B: Adds galactose (Gal) to H antigen (galactosyltransferase). Type AB: Both enzymes active. Type O: Neither enzyme functional; only the unmodified H antigen is present. The difference between a type A and type B transferase is just 4 amino acid substitutions.
Key Concepts Summary
Classification: Carbohydrates are polyhydroxy aldehydes (aldoses) or ketones (ketoses), classified as monosaccharides, disaccharides, oligosaccharides, or polysaccharides. General formula: (CH2O)n.
Stereochemistry: Monosaccharides with $n$ chiral centers have $2^n$ stereoisomers. D/L designation is based on the highest-numbered chiral center. Epimers differ at one chiral center.
Cyclization: Monosaccharides form pyranose (6-membered) or furanose (5-membered) rings. The anomeric carbon creates α (axial OH) and β (equatorial OH) anomers that interconvert via mutarotation.
Sugar Derivatives: Sugar acids, sugar alcohols, deoxy sugars, amino sugars, and phosphorylated sugars are essential for metabolism, structural biology, and cell signaling.
Glycosidic Bonds: Covalent bonds between anomeric carbon and hydroxyl group. Bond type (α vs. β, carbon positions) determines biological properties. Reducing sugars have a free anomeric carbon.
Polysaccharides: Storage: starch (α1→4 with α1→6 branches) and glycogen (highly branched). Structural: cellulose (β1→4, indigestible), chitin (β1→4 GlcNAc), peptidoglycan (bacterial cell wall).
Glycoconjugates: Glycoproteins (N-linked and O-linked), proteoglycans with GAG chains (heparin, chondroitin sulfate, hyaluronic acid), glycolipids (cerebrosides, gangliosides). ABO blood types are determined by terminal sugars.