Carbohydrates: Structure, Function, and Reactions

Biochemistry Overview

Biochemistry Definition: The study of chemical substances found in living organisms and the chemical interactions of these substances with each other.
Biochemical Substance: Any chemical substance found within a living organism.
Classification of Biochemical Substances:
- Bioinorganic Substances: Water and inorganic salts.
- Bioorganic Substances: Carbohydrates, lipids, proteins, and nucleic acids.
Life Sustaining Properties: As isolated compounds, bioinorganic and bioorganic substances possess no life in and of themselves. When these substances are gathered together in a cell, their chemical interactions are able to sustain life.

Occurrence and Functions of Carbohydrates

Plant Occurrence and Uses:
- More than half of all organic carbon atoms are found in the carbohydrate materials of plants.
- Carbohydrates account for $75\%$ of dry plant material.
- Plants produce carbohydrates via photosynthesis using solar energy, carbon dioxide, and water: $CO_2 + H_2O + \text{solar energy} \xrightarrow{\text{chlorophyll, plant enzymes}} \text{carbohydrates} + O_2$
- Cellulose serves as a structural element in plants.
- Starch serves as an energy reservoir in plants.
- Human non-food uses of plant carbohydrates include cotton and linen for clothing, and wood for shelter, heating, and paper manufacturing.
Functions of Carbohydrates in the Human Body:
- Carbohydrate oxidation provides energy for physiological processes.
- Carbohydrate storage in the form of glycogen provides a short-term energy reserve.
- Carbohydrates supply carbon atoms for the synthesis of other biochemical substances (proteins, lipids, and nucleic acids).
- Carbohydrates form part of the structural framework of $DNA$ and $RNA$ molecules.
- Carbohydrates linked to lipids (glycolipids) serve as structural components of cell membranes.
- Carbohydrates linked to proteins (glycoproteins) function in a variety of cell-cell and cell-molecule recognition processes.

Classification of Carbohydrates

Chemical Definition: A polyhydroxy aldehyde, a polyhydroxy ketone, or a compound that produces such substances upon hydrolysis.
Empirical Formula: Simple carbohydrates have the general empirical formula $C_n H_{2n} O_n$ or $C_n(H_2O)_n$ (a hydrate of carbon, where $n$ represents the number of carbon atoms).
Categories Based on Monosaccharide Units:
- Monosaccharides:
- Contain a single polyhydroxy aldehyde or ketone unit.
- Cannot be broken down into simpler substances by hydrolysis reactions.
- Contain $3$ to $7$ carbon atoms; $5$ -carbon and $6$ -carbon species are most common.
- Pure monosaccharides are water-soluble, white, crystalline solids.
- Examples: Glucose, fructose.
- Disaccharides:
- Contain $2$ monosaccharide units covalently bonded to each other.
- Crystalline and water-soluble substances.
- Yield $2$ monosaccharide units upon hydrolysis.
- Examples: Sucrose (table sugar), lactose (milk sugar).
- Oligosaccharides:
- Contain $3$ to $10$ monosaccharide units covalently bonded to each other.
- Free oligosaccharides are seldom encountered in biological systems; usually associated with proteins and lipids in complex molecules that serve structural and regulatory functions.
- Polysaccharides:
- Contain many monosaccharide units covalently bonded (ranging from a few hundred to $50,000$ units).
- Examples: Cellulose (paper, cotton, wood), starch (bread, pasta, potatoes, rice, corn, beans, peas).

Chirality: Handedness in Molecules

Molecular Handedness:
- Most biological molecules, including carbohydrates, exhibit handedness (a form of stereoisomerism).
- Handed molecules exist in "left-handed" and "right-handed" forms related as mirror images.
Mirror Image Classes:
- Superimposable Mirror Images: Images where all points coincide when laid upon each other; indicates an achiral molecule (lacks handedness).
- Nonsuperimposable Mirror Images: Images where not all points coincide when laid upon each other; indicates a chiral molecule (possesses handedness).
Chiral Centers:
- A chiral center is a carbon atom attached to $4$ different groups.
- A molecule possessing a chiral center is chiral.
- A chiral carbon atom is denoted by an asterisk ( $*$ ).
- Example: Bromochloroiodomethane is a simple chiral organic molecule.
Biological Responses to Handedness:
- Enantiomers react differently in chiral biological environments. Both forms may be active, one may be more active, or one may be active while the other is inactive.
- The human body's response to the right-handed hormone epinephrine is $20\times$ greater than its response to the left-handed form.
- Almost all naturally occurring monosaccharides are right-handed ( $D$ -form).
- Naturally occurring amino acids are left-handed ( $L$ -form).

Stereoisomerism: Enantiomers and Diastereomers

Stereoisomers: Isomers that have identical molecular and structural formulas but differ in the spatial orientation of their atoms.
Types of Stereoisomers:
- Enantiomers: Stereoisomers whose molecules are nonsuperimposable mirror images of each other (requires the presence of a chiral center).
- Diastereomers: Stereoisomers whose molecules are not mirror images of each other (e.g., cis-trans isomers, epimers).

Designating Handedness Using Fischer Projection Formulas

Fischer Projection Formula: A two-dimensional structural notation used to show the spatial arrangement of groups around chiral centers in molecules.
Structural Conventions:
- A chiral center is represented as the intersection of vertical and horizontal lines.
- High-priority functional groups are positioned at the top of the formula.
- Vertical lines represent bonds directed into the printed page.
- Horizontal lines represent bonds directed out of the printed page.
$D, L$ Configuration Assignment:
- The $D$ and $L$ designation is based on the reference compound glyceraldehyde.
- For monosaccharides containing multiple chiral centers (e.g., 2,3,4-trihydroxybutanal, which has $4$ carbons, $2$ chiral centers, $4$ stereoisomers, and $2$ pairs of enantiomers):
1. Number the carbon chain starting at the carbonyl group end.
2. Locate the highest-numbered chiral center (the chiral carbon farthest from the carbonyl group).
3. If the $-OH$ group on this carbon points to the right, the molecule is the $D$ -isomer.
4. If the $-OH$ group on this carbon points to the left, the molecule is the $L$ -isomer.
Epimers: Diastereomers whose molecules differ in configuration at only one chiral center.

Properties of Enantiomers

Comparison with Other Isomers:
- Constitutional Isomers: Differ in most physical and chemical properties (e.g., different boiling points and melting points).
- Diastereomers: Differ in most physical and chemical properties (e.g., different boiling points and freezing points).
- Enantiomers: Possess identical physical properties (boiling point, melting point, density) and identical chemical properties in achiral environments because these properties depend on intermolecular forces which are unaffected by chirality.
Distinguishing Differences Between Enantiomers:
1. Interaction with plane-polarized light.
2. Interaction with other chiral substances (e.g., enantiomers display identical solubility in achiral solvents like ethanol, but different solubility in chiral solvents like $D$ -2-butanol).
Optical Activity:
- Ordinary light waves vibrate in all directions perpendicular to the direction of travel.
- Plane-polarized light waves vibrate in only one plane.
- Enantiomers are optically active compounds because they rotate the plane of polarized light.
- Dextrorotatory Compound ( $+$ ): A chiral compound that rotates plane-polarized light clockwise (to the right).
- Levorotatory Compound ( $-$ ): A chiral compound that rotates plane-polarized light counterclockwise (to the left).
- Note: There is no direct correlation between $D/L$ structural designation and $+/-$ optical rotation. $D/L$ is determined by structural formulas, whereas $+/-$ is measured experimentally using a polarimeter.
- Equal concentrations of enantiomer pairs rotate light to the exact same extent, but in opposite directions.

Classification of Monosaccharides

Classification by Carbon Count:
- Triose: $3$ carbon atoms
- Tetrose: $4$ carbon atoms
- Pentose: $5$ carbon atoms
- Hexose: $6$ carbon atoms
Classification by Functional Group:
- Aldose: Monosaccharide containing an aldehyde group.
- Ketose: Monosaccharide containing a ketone group.
Combined Classification Examples:
- Aldohexose: Monosaccharide with an aldehyde group and $6$ carbon atoms.
- Ketopentose: Monosaccharide with a ketone group and $5$ carbon atoms.
- Aldotetrose: Monosaccharide with an aldehyde group and $4$ carbon atoms.
- Ketohexose: Monosaccharide with a ketone group and $6$ carbon atoms.

Biochemically Important Monosaccharides

$D$ -Glucose:
- Aldohexose; the most abundant monosaccharide in nature and the most important source of human nutrition.
- Found in high concentration in ripe fruits and grapefruits ( $20\% - 30\%$ by mass); also known as grape sugar.
- Also called dextrose or blood sugar (normal human blood glucose levels range from $70 - 100\,mg/dL$ ).
- Forms a six-membered cyclic ring.
$D$ -Galactose:
- Aldohexose; synthesized in humans and component of milk sugar.
- Also called brain sugar as it is a constituent of brain and nerve tissue.
- Used to differentiate human blood types.
- Forms a six-membered cyclic ring.
$D$ -Fructose:
- Ketohexose; the sweetest tasting of all sugars.
- Found in fruits and honey; excellent dietary sugar due to high sweetness.
- Forms a five-membered cyclic ring.
$D$ -Ribose:
- Aldopentose; structural component of complex bioorganic molecules including $RNA$ , $ATP$ , and $DNA$ (as deoxyribose).
- Forms a five-membered cyclic ring.

Cyclic Forms of Monosaccharides and Haworth Projections

Cyclic Hemiacetal Formation:
- In aqueous solution, monosaccharides containing $5$ or more carbon atoms exist predominantly in cyclic hemiacetal forms in dynamic equilibrium with their open-chain forms.
- Formed by an intramolecular reaction between the carbonyl carbon ( $C=O$ ) and the hydroxyl group ( $-OH$ ) attached to carbon 5 ( $C5$ ).
Anomers and Anomeric Carbon:
- Anomeric Carbon: The hemiacetal carbon carbon-1 ( $C1$ ) formed from the original carbonyl carbon.
- Anomers: Cyclic monosaccharides that differ only in the spatial orientation of substituents on the anomeric carbon atom.
- $\alpha$ -Anomer: The $-OH$ group on $C1$ points in the opposite direction relative to the $-CH_2OH$ group attached to $C5$ .
- $\beta$ -Anomer: The $-OH$ group on $C1 $points in the same direction relative to the$ -CH_2OH $group attached to$ C5.\n\n* **Ring Terminology**:\n * **Pyranose**: A cyclic monosaccharide containing a 6-atom ring (resembles pyran).\n * **Furanose**: A cyclic monosaccharide containing a 5-atom ring (resembles furan).\n\n* **Haworth Projection Conventions**:\n * A two-dimensional structural notation specifying the three-dimensional structure of a cyclic monosaccharide.\n * Any substituent pointing to the **right** in a Fischer projection formula points **down** in the corresponding Haworth projection formula.\n * Any substituent pointing to the **left** in a Fischer projection formula points **up** in the corresponding Haworth projection formula.\n * Structural characteristics of specific monosaccharides:\n * D-Glucose: Forms a 6-membered pyranose ring.\n * D-Galactose: Forms a 6-membered pyranose ring.\n * D $-Fructose: Forms a 5-membered furanose ring with$ 2 $carbon atoms ($ C1 $and$ C6) located outside the ring.\n * D-Ribose: Forms a 5-membered furanose ring.\n\n\n# Reactions of Monosaccharides\n\n* **Oxidation to Acidic Sugars**:\n * **Aldonic Acid**: Produced when weak oxidizing agents (e.g., Tollens or Benedict's solutions) oxidize the aldehyde group at C1 to a carboxylic acid.\n * **Reducing Sugar**: Any carbohydrate that reduces weak oxidizing agents like Tollens or Benedict's reagents under basic conditions, yielding a positive test. All aldoses and ketoses (e.g., glucose, fructose, mannose) act as reducing sugars.\n * **Aldaric Acid**: Polyhydroxy dicarboxylic acid produced when strong oxidizing agents oxidize both ends of the monosaccharide simultaneously (the carbonyl carbon C1 $and the terminal primary alcohol carbon$ C6).\n * **Alduronic Acid**: Produced when enzymes selectively oxidize the terminal primary alcohol group (C6 $) without oxidizing the aldehyde group at$ C1.\n\n* **Reduction to Sugar Alcohols (Alditols)**:\n * Carbonyl groups of aldoses and ketoses are reduced to hydroxyl groups using hydrogen gas (H_2) in the presence of catalysts.\n * Product is a polyhydroxy alcohol termed a **sugar alcohol** or **alditol**.\n * **Sorbitol**: Sugar alcohol produced from glucose reduction; used as a moisturizing agent in foods and cosmetics, and as a sweetener in sugar-free chewing gum.\n\n* **Glycoside Formation**:\n * An acetal formed when the hemiacetal -OH $group of a cyclic monosaccharide reacts with an alcohol ($ -OR group).\n * Glucoside: A glycoside derived from glucose.\n * Galactoside: A glycoside derived from galactose.\n * Glycosides exist in both \alpha $and$ \beta configurations.\n\n* **Phosphate Ester Formation**:\n * Hydroxyl groups of monosaccharides react with inorganic oxyacids (such as phosphoric acid) to yield phosphate esters.\n * Monosaccharide phosphate esters are stable in aqueous solution and serve as metabolic intermediates in carbohydrate pathways.\n\n* **Amino Sugar Formation**:\n * Formed when a hydroxyl group of a monosaccharide is replaced by an amino group (-NH_2).\n * In naturally occurring amino sugars, the C2 hydroxyl group is substituted.\n * Amino sugars and their N-acetyl derivatives serve as essential building blocks for complex polysaccharides like chitin and hyaluronic acid.\n\n\n# Disaccharides\n\n* **Structure and Bonding**:\n * Formed when two monosaccharide units react; one unit acts as a hemiacetal and the other acts as an alcohol.\n * The resulting ether linkage connecting the two rings is called a **glycosidic linkage**.\n\n* **Maltose (Malt Sugar)**:\n * Composed of 2D $-glucose units, one of which must be$ \alpha $-$ D-glucose.\n * Joined by an \alpha(1 \rightarrow 4) glycosidic linkage.\n * Easily digested by humans due to enzymes capable of cleaving \alpha(1 \rightarrow 4) bonds.\n * Prevalent in baby foods; acts as a reducing sugar.\n\n* **Cellobiose**:\n * Intermediate produced during the hydrolysis of cellulose.\n * Composed of 2D $-glucose units, one of which must have a$ \beta configuration.\n * Joined by a \beta(1 \rightarrow 4) glycosidic linkage.\n * Cannot be digested by humans; acts as a reducing sugar.\n\n* **Lactose (Milk Sugar)**:\n * Composed of a \beta $-$ D $-galactose unit and a$ D-glucose unit.\n * Joined by a \beta(1 \rightarrow 4) glycosidic linkage.\n * Principal carbohydrate in milk: Human mother's milk contains 7\% - 8\% $lactose; cow's milk contains$ 4\% - 5\% lactose.\n * Hydrolyzed by the enzyme lactase; acts as a reducing sugar.\n * **Lactose Intolerance**:\n * Condition caused by a deficiency of the lactase enzyme, stemming from genetic defects, age-related physiological decline, or mucosal damage.\n * Undigested lactose causes water retention in the lumen (leading to bloating, cramping, nausea, and diarrhea) and undergoes bacterial fermentation in the colon to produce lactic acid and gas.\n\n* **Sucrose (Table Sugar)**:\n * Most abundant disaccharide in nature, found widely in plants.\n * Commercially extracted from sugar cane (up to 20\% $sucrose by mass) and sugar beets (up to$ 17\% sucrose by mass).\n * Composed of an \alpha $-$ D $-glucose unit and a$ \beta $-$ D $-fructose unit joined by a head-to-head$ \alpha,\beta(1 \rightarrow 2) glycosidic bond.\n * **Non-reducing sugar** because both anomeric carbons are tied up in the glycosidic linkage.\n\n\n# Oligosaccharides\n\n* **General Characteristics**:\n * Contain 3 $to$ 10 monosaccharide units linked via glycosidic bonds.\n * Seldom found free in nature; usually conjugated with lipids or proteins.\n * **Raffinose**: Trisaccharide composed of 1 $galactose,$ 1 $glucose, and$ 1 fructose unit.\n * **Stachyose**: Tetrasaccharide composed of 2 $galactose,$ 1 $glucose, and$ 1 fructose unit.\n * Abundant in onions, cabbage, broccoli, and whole wheat.\n * **Solanine**: Potato plant toxin comprising an oligosaccharide linked to an alkaloid; gives potatoes a bitter taste when present in high concentrations.\n\n* **Blood Types and Oligosaccharides**:\n * Human blood is classified into four major types: A, B, AB, and O.\n * Differences depend on specific oligosaccharides displayed on the plasma membranes of red blood cells.\n * D-Galactose and its structural derivatives form the biochemical basis of these blood group determinants.\n * Type O individuals are **universal donors**; Type AB individuals are **universal recipients**.\n * Transfusion of incompatible blood causes cell clumping (agglutination), which can be fatal.\n * Prevalence in the United States: Type O is the most common, followed by Type A.\n\n\n# General Characteristics of Polysaccharides\n\n* **Polymer Chain Structure**:\n * Polymers composed of many monosaccharide units bonded via glycosidic linkages.\n * **Homopolysaccharide**: Polysaccharide containing only one type of monosaccharide monomer.\n * **Heteropolysaccharide**: Polysaccharide containing two or more different types of monosaccharide monomers.\n\n* **General Physical & Chemical Properties**:\n * Polysaccharides are not sweet tasting.\n * Give negative tests with Tollens and Benedict's solutions.\n * Exhibit limited water solubility.\n\n\n# Storage Polysaccharides\n\n* **Definition**: Polysaccharides that function as energy storage forms in living cells.\n\n* **Starch**:\n * Plant storage polysaccharide composed entirely of D-glucose monomers.\n * Consists of two separable fractions:\n * **Amylose**: Unbranched linear polymer making up 15\% - 20\% $of starch; contains$ \alpha(1 \rightarrow 4) glycosidic linkages.\n * **Amylopectin**: Highly branched polymer making up 80\% - 85\% $of starch; contains$ \alpha(1 \rightarrow 4) $linkages in linear chains and$ \alpha(1 \rightarrow 6) $linkages at branch points. Contains up to$ 100,000 glucose units. Digested more rapidly by humans than amylose.\n\n* **Glycogen**:\n * Glucose storage polysaccharide in humans and animals.\n * Highly branched polymer of D $-glucose containing$ \alpha(1 \rightarrow 4) $linkages in straight chains and$ \alpha(1 \rightarrow 6) linkages at branch points.\n * 3\times $more highly branched than amylopectin in starch; contains up to$ 1,000,000 glucose units.\n * **Glycogenesis**: Metabolic process converting excess blood glucose into stored glycogen.\n * **Glycogenolysis**: Metabolic breakdown of stored glycogen into glucose when blood glucose levels drop.\n\n\n# Structural Polysaccharides\n\n* **Definition**: Polysaccharides serving as structural components in cell walls and exoskeletons.\n\n* **Cellulose**:\n * Linear homopolysaccharide of D $-glucose containing$ \beta(1 \rightarrow 4) glycosidic linkages.\n * Contains up to 5,000 $glucose units with an average molecular mass of approximately$ 900,000\,\text{amu}.\n * Cotton contains 95\% $cellulose; wood contains$ 50\% cellulose.\n * Humans cannot digest cellulose because human digestive enzymes lack the ability to hydrolyze \beta(1 \rightarrow 4) linkages.\n * Animals (e.g., ruminants) digest cellulose via symbiotic cellulase-producing bacteria in their digestive tracts.\n * Serves as dietary fiber in humans, absorbing water to yield soft stool bulk. Recommended daily intake is 20 - 35\,g.\n\n* **Chitin**:\n * Linear homopolysaccharide with \beta(1 \rightarrow 4) glycosidic linkages.\n * Composed of monomer units of N $-acetyl-$ D $-glucosamine (an$ N-acetyl amino derivative of glucose).\n * Functions to provide structural rigidity to the exoskeletons of crabs, lobsters, shrimp, insects, and other arthropods.\n\n\n# Acidic Polysaccharides\n\n* **Definition**: Heteropolysaccharides with a repeating disaccharide pattern consisting of an amino sugar and a sugar bearing a negative charge due to a sulfate or carboxyl group.\n\n* **Hyaluronic Acid**:\n * Alternating residues of N $-acetyl-$ \beta $-$ D $-glucosamine and$ D-glucuronate.\n * Highly viscous substance that serves as a lubricant in joint fluids (synovial fluid) and in the vitreous humor of the eye.\n\n* **Heparin**:\n * Composed of 15 - 90 disaccharide residues per chain.\n * Functions biochemically as a potent anticoagulant (prevents blood clotting).\n\n\n# Dietary Considerations and Carbohydrates\n\n* **Global Dietary Contribution**:\n * Carbohydrate-rich foods constitute over 50\% of the diet for most global human populations (e.g., corn in South America, rice in Asia, starchy root crops in Africa, potatoes and wheat in North America).\n * A balanced human diet should derive approximately 60\% of its energy from carbohydrates.\n\n* **Categories of Dietary Carbohydrates**:\n * **Simple Carbohydrates**: Dietary monosaccharides or disaccharides; sweet-tasting sugars that contribute 20\% of total energy in the U.S. diet.\n * **Complex Carbohydrates**: Dietary polysaccharides (starch and cellulose); generally non-sweet.\n\n\n# Glycolipids and Glycoproteins: Cell Recognition\n\n* **Glycolipids**: Lipid molecules containing one or more covalently bound carbohydrate (or carbohydrate derivative) units.\n\n* **Glycoproteins**: Protein molecules containing one or more covalently bound carbohydrate (or carbohydrate derivative) units.\n\n* **Biological Function**: Glycolipids and glycoproteins embedded in cell membranes are critical for cell recognition, cell-cell signaling, and cell-molecule binding processes.\n\n\n# Review Questions & Conceptual Exercises\n\n* **Determining D-Glucose Stereoisomers**:\n * *Question*: D $-glucose consists of six carbon atoms. When drawn using the Fischer projection formula, how is the$ D isomer determined? How many chiral carbon centers does it have and how many stereoisomers are possible?\n * *Answer*: The -OH $on the chiral carbon farthest from the carbonyl group ($ C5 $) points to the right. There are$ 4 $chiral centers, providing$ 2^4 = 16$$ possible stereoisomers.
Mechanism and Importance of Carbohydrate Loading:
- Question: Prior to a marathon, an athlete consumes large amounts of complex carbohydrates to "carbohydrate load." What happens in the body to the glucose molecules present in these carbohydrates, and why is this important?
- Answer: The complex carbohydrates are hydrolyzed into glucose monomers. Any excess glucose not used immediately for energy is converted via glycogenesis and stored in the body in the form of glycogen, which provides a readily accessible energy reservoir during prolonged exertion.