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Carbohydrate Classification: Aldose

A monosaccharide with a carbonyl group (aldehyde) at C-1; e.g., glucose.

Carbohydrate Classification: Ketose

A monosaccharide with a carbonyl group (ketone) at C-2; e.g., fructose.

D vs L Configuration in Sugars

Determined by the highest-numbered chiral carbon: -OH on the right = D; -OH on the left = L; human sugars are D.

Constitutional Isomers

Sugars with the same formula but different connectivity; e.g., glucose (aldose) vs fructose (ketose).

Enantiomers

Stereoisomers that are non-superimposable mirror images; e.g., D-glucose vs L-glucose.

Diastereomers

Stereoisomers that are not mirror images; e.g., glucose vs galactose vs mannose.

Epimers

Diastereomers that differ at exactly one chiral center; e.g., galactose (C-4) and mannose (C-2) are glucose epimers.

Anomers

Epimers that differ only at the anomeric carbon created on ring closure; e.g., α-D-glucose vs β-D-glucose.

Cyclization of Glucose

C-5 -OH attacks C-1 carbonyl, forming a six-membered pyranose ring; creates a new chiral center at the anomeric carbon (C-1).

Cyclization of Fructose

C-5 -OH attacks C-2 carbonyl, forming a five-membered furanose ring; C-2 becomes the anomeric carbon.

α vs β Anomer

α: anomeric -OH is down (trans to CH2OH); β: anomeric -OH is up (cis to CH2OH) in Haworth projection.

Mutarotation

Interconversion of α and β anomers through the open-chain form; equilibrium ~63% β, ~36% α, <1% open chain.

Reducing Sugar

A sugar with a free anomeric carbon that can open to an aldehyde and reduce Cu²⁺ (Benedict's test); all monosaccharides are reducing.

Glycosidic Bond

Bond formed by condensation between the anomeric -OH of one sugar and an -OH of another; can be O-linked or N-linked.

O-Glycosidic Bond

Bond between the anomeric carbon and a hydroxyl group (sugar-sugar or sugar-Ser/Thr).

N-Glycosidic Bond

Bond between the anomeric carbon and a nitrogen base (nucleotides) or Asn (N-linked glycoproteins).

Reducing End

A free anomeric carbon at the end of a polysaccharide chain that can open and reduce.

Non-Reducing Sugar

A sugar with no free anomeric carbon (both tied up in glycosidic bonds); e.g., sucrose.

Maltose

Disaccharide: Glc-α(1→4)-Glc; reducing; produced by starch digestion; cleaved by maltase.

Lactose

Disaccharide: Gal-β(1→4)-Glc; reducing; milk sugar; cleaved by lactase (β-galactosidase).

Sucrose

Disaccharide: Glc-α(1↔2)β-Fru; non-reducing; cane/beet sugar; cleaved by sucrase.

Sucrose Cariogenicity

S. mutans glucosyltransferases split sucrose to build sticky, insoluble glucans (plaque matrix) and release fermentable sugars for acid production.

Stephan Curve

Plaque pH falls below critical 5.5 within minutes of sugar exposure and recovers over 30-60 min; frequency of exposure matters more than amount.

Amylose

Linear α(1→4)-linked glucose polymer in starch; coils into helices.

Amylopectin

α(1→4)-linked glucose with α(1→6) branches every 24-30 residues in starch.

Glycogen

Animal glucose store; α(1→4)-linked with α(1→6) branches every 8-12 residues; many non-reducing ends for rapid release.

Cellulose

β(1→4)-linked glucose polymer; indigestible by humans (dietary fiber); no human enzyme cleaves β(1→4) bonds.

Salivary Mucins (MUC5B, MUC7)

Heavily O-glycosylated proteins that lubricate oral tissues, form acquired pellicle, and aggregate bacteria.

Glycosaminoglycans (GAGs)

Long unbranched repeats of amino sugar + uronic acid; sulfated → strongly negative → hold water; ground substance of gingiva, PDL, cartilage.

ABO Blood Group Antigens

Shared H core (…Gal + Fuc); A adds GalNAc, B adds Gal, O adds nothing; one terminal sugar changes the antigen.

Lysozyme

Salivary/tear enzyme that hydrolyzes β(1→4) bond between NAM and NAG in peptidoglycan, lysing bacteria (especially Gram-positive).

Carbohydrate Digestion: Mouth

Salivary α-amylase (ptyalin) cleaves internal α(1→4) bonds → maltose, maltotriose, α-limit dextrins; cannot cut α(1→6).

Carbohydrate Digestion: Stomach

Gastric acid (pH 1.5-3.5) denatures salivary amylase; little carbohydrate digestion occurs.

Carbohydrate Digestion: Small Intestine Lumen

Pancreatic bicarbonate neutralizes chyme; pancreatic α-amylase completes starch digestion to maltose, maltotriose, α-limit dextrins.

Carbohydrate Digestion: Brush Border

Maltase, sucrase, isomaltase, lactase hydrolyze disaccharides to monosaccharides; only monosaccharides are absorbed.

SGLT1

Apical Na⁺-coupled secondary active transporter for glucose/galactose in enterocytes; driven by Na⁺ gradient from basolateral Na⁺/K⁺-ATPase.

GLUT5

Apical facilitated diffusion transporter for fructose in enterocytes.

GLUT2

Basolateral facilitated diffusion transporter releasing glucose, galactose, fructose to blood; high capacity, low affinity; also liver/β-cell glucose sensor.

GLUT1

High-affinity, always-active glucose transporter in brain, red cells, most cells.

GLUT4

Insulin-responsive glucose transporter in skeletal muscle and adipose; moves to membrane upon insulin signal.

Lactose Intolerance

Lactase deficiency → lactose reaches colon → osmotic water retention (diarrhea) and bacterial fermentation (gas, organic acids).

Glycolysis: Net Yield

Per glucose: 2 ATP, 2 NADH, 2 pyruvate; occurs in cytosol; no O₂ required.

Glycolysis: Three Irreversible Steps

Hexokinase/glucokinase (glucose→G6P), PFK-1 (F6P→F1,6BP), pyruvate kinase (PEP→pyruvate).

Hexokinase

Low Km (~0.1 mM), saturated at normal blood glucose; inhibited by G6P; in most tissues; guarantees cells glucose.

Glucokinase

High Km (~10 mM), not inhibited by G6P; in liver and pancreatic β-cells; glucose sensor; induced by insulin.

PFK-1 Regulation

Inhibited by ATP and citrate; activated by AMP and fructose-2,6-bisphosphate (most potent); insulin raises F2,6BP; glucagon lowers it.

Fructose-2,6-bisphosphate

Master switch: activates PFK-1 and inhibits FBPase-1; high when fed (insulin), low when fasting (glucagon).

Pyruvate Kinase

Third irreversible step: PEP → pyruvate + ATP; activated by fructose-1,6-bisphosphate (feedforward); inhibited by ATP.

Aerobic Fate of Pyruvate

Pyruvate → mitochondria → PDH → acetyl-CoA → citric acid cycle → ~30-32 ATP per glucose.

Anaerobic Fate of Pyruvate

Pyruvate + NADH → lactate (lactate dehydrogenase); regenerates NAD⁺ for glycolysis; only 2 ATP per glucose.

Lactate Dehydrogenase (LDH)

Converts pyruvate to lactate, oxidizing NADH to NAD⁺; essential when oxygen is limited (exercising muscle, RBCs, plaque bacteria).

S. mutans Fermentation

S. mutans lacks respiratory chain; regenerates NAD⁺ by converting pyruvate to lactate; only 2 ATP per glucose → must ferment a lot of sugar → releases a lot of acid → plaque pH 4.5-5.5.

Fluoride Mechanism in Plaque

Enters bacteria as HF in acidic plaque, releases F⁻ inside; inhibits enolase (step 9) → less PEP, pyruvate, lactate; also less PEP-driven sugar uptake; main benefit is on enamel (fluorapatite, remineralization).

Xylitol Mechanism in Plaque

Taken up and phosphorylated by PEP-driven sugar transport system; xylitol-5-P cannot enter glycolysis → futile cycle wastes bacterial energy; less growth and less acid.

Red Cell Glycolysis

No mitochondria; glycolysis is only ATP source; lactate is end product; 2,3-BPG shunt diverts 1,3-BPG to 2,3-BPG (costs one ATP).

2,3-BPG Shunt

In red cells: 1,3-BPG → 2,3-BPG; 2,3-BPG binds deoxyhemoglobin, stabilizes it, shifts O₂ curve right → more O₂ released to tissues.

Fructose Entry into Glycolysis

Fructokinase → fructose-1-P → aldolase B → DHAP + glyceraldehyde → G3P; enters below PFK-1, skipping main control point.

Galactose Entry into Glycolysis

Galactokinase → galactose-1-P → UDP-galactose → epimerase inverts C-4 → UDP-glucose → glucose-6-P.

PDH Complex

Pyruvate + CoA + NAD⁺ → acetyl-CoA + CO₂ + NADH; in mitochondrial matrix; irreversible; requires TPP (B1), lipoic acid, CoA (B5), FAD (B2), NAD⁺ (B3).

PDH Regulation

Phosphorylation by PDH kinase → OFF; dephosphorylation by PDH phosphatase → ON; products (acetyl-CoA, NADH, ATP) inhibit; pyruvate, ADP, Ca²⁺ activate.

Citric Acid Cycle: Per Turn

Per turn: 3 NADH, 1 FADH₂, 1 GTP, 2 CO₂; oxaloacetate regenerated; two turns per glucose.

Citrate Synthase

Entry step: acetyl-CoA (2C) + oxaloacetate (4C) → citrate (6C); slowed by ATP, NADH, succinyl-CoA, citrate.

Isocitrate Dehydrogenase

Rate-limiting enzyme of CAC: isocitrate → α-ketoglutarate + NADH + CO₂; activated by ADP and Ca²⁺; inhibited by ATP and NADH.

α-Ketoglutarate Dehydrogenase

α-KG → succinyl-CoA + NADH + CO₂; same five cofactors as PDH; inhibited by NADH and succinyl-CoA; activated by Ca²⁺.

Succinate Dehydrogenase

Succinate → fumarate; also Complex II of electron transport chain; produces FADH₂; pumps no protons.

CAC ATP Yield per Glucose

~30-32 ATP aerobic: 10 NADH × 2.5 + 2 FADH₂ × 1.5 + 4 ATP/GTP (substrate level); 2 ATP anaerobic.

Anaplerosis

Replenishment of CAC intermediates withdrawn for biosynthesis; main enzyme: pyruvate carboxylase (pyruvate → oxaloacetate; biotin; activated by acetyl-CoA).

Pyruvate Carboxylase

Pyruvate + CO₂ → oxaloacetate; requires biotin; activated by acetyl-CoA; main anaplerotic enzyme; also first bypass in gluconeogenesis.

Why Fat Cannot Make Glucose

Even-chain fatty acids give only acetyl-CoA; PDH irreversible; CAC gives no net oxaloacetate (2C in, 2 CO₂ out); no net glucose.

B Vitamins and CAC

B1 → TPP (PDH, α-KGDH); B2 → FAD (PDH, α-KGDH, succinate DH); B3 → NAD⁺ (PDH, isocitrate DH, α-KGDH, malate DH); B5 → CoA (PDH, α-KGDH).

Riboflavin (B2) Deficiency Oral Signs

Angular cheilitis, glossitis, sore red lips; FAD needed by PDH, α-KGDH, succinate DH.

Niacin (B3) Deficiency Oral Signs

Pellagra: red, swollen, sore tongue; stomatitis; NAD⁺ needed by PDH, isocitrate DH, α-KGDH, malate DH.

Arsenic Poisoning

Binds lipoic acid, disabling PDH and α-ketoglutarate dehydrogenase; pyruvate backs up into lactate.

Fluoroacetate Poisoning

Converted to fluorocitrate, which blocks aconitase (step 2 of CAC); citrate accumulates.

Gluconeogenesis: Why It Exists

Brain (~120 g/day) and red cells depend on glucose; liver glycogen (~100 g) lasts only 12-18 h of fasting; mainly liver (~90%), some kidney.

Gluconeogenesis Substrates

Lactate, glucogenic amino acids (mainly alanine), glycerol from fat; NOT even-chain fatty acids.

Gluconeogenesis: Four Bypass Enzymes

Pyruvate carboxylase (mitochondria; biotin), PEPCK (cytosol; GTP), Fructose-1,6-bisphosphatase (rate-limiting), Glucose-6-phosphatase (ER of liver/kidney only).

Fructose-1,6-Bisphosphatase (FBPase-1)

Rate-limiting enzyme of gluconeogenesis: F1,6BP → F6P; inhibited by fructose-2,6-bisP and AMP; activated by citrate and (indirectly) glucagon.

Glucose-6-Phosphatase

Glucose-6-P → glucose + Pi in ER of liver and kidney only; absent in muscle; deficiency = von Gierke disease.

Cost of Gluconeogenesis

2 pyruvate + 4 ATP + 2 GTP + 2 NADH → glucose (6 high-energy phosphates spent; glycolysis yields only 2 ATP back).

Cori Cycle

Lactate from red cells and working muscle → liver → glucose → back to tissues; liver spends 6 ATP, muscle gains 2.

Glucose-Alanine Cycle

Muscle converts pyruvate to alanine; liver converts alanine to pyruvate → glucose; nitrogen becomes urea.

Pentose Phosphate Pathway: Products

NADPH and ribose-5-phosphate; no ATP made or used; cytosolic.

PPP Oxidative Phase

Irreversible: glucose-6-P → ribulose-5-P + CO₂ + 2 NADPH; G6PD is rate-limiting.

PPP Non-Oxidative Phase

Reversible: transketolase (needs thiamine, B1) and transaldolase swap sugars between pentoses and glycolytic intermediates.

G6PD (Glucose-6-Phosphate Dehydrogenase)

Rate-limiting, committed step of PPP; makes first NADPH; activated when NADP⁺ is high; deficiency → oxidative hemolysis (red cells have no mitochondria, PPP is only NADPH source).

NADPH Functions

Biosynthesis (fatty acids, cholesterol, steroids); keeps glutathione reduced to destroy H₂O₂; neutrophil respiratory burst (NADPH oxidase makes superoxide to kill bacteria).

Ribose-5-Phosphate Function

Nucleotides for DNA and RNA in dividing cells (healing gingiva, oral mucosa).

Heavy Alcohol Use and Hypoglycemia

Alcohol metabolism raises NADH → pyruvate to lactate, oxaloacetate to malate → gluconeogenesis stalls → fasting hypoglycemia.

Glycogen Structure

α(1→4) chains with α(1→6) branches every 8-12 glucoses; built on glycogenin protein primer; one reducing end, many non-reducing ends where enzymes act.

Glycogen Synthase

Rate-limiting enzyme of glycogen synthesis; adds glucose from UDP-glucose to non-reducing end (α1→4); activated by insulin (dephosphorylation).

Glycogen Phosphorylase

Rate-limiting enzyme of glycogen breakdown; uses Pi to cleave α(1→4) bonds → glucose-1-P; requires pyridoxal phosphate (B6); activated by phosphorylation (glucagon/epinephrine).

Debranching Enzyme

Two activities: transferase (moves 3 of last 4 glucoses to another chain) and α(1→6) glucosidase (cuts last glucose off branch as free glucose).

Liver vs Muscle Glycogen

Liver (~100 g): has glucose-6-phosphatase → releases glucose to blood; responds to glucagon. Muscle (~400 g): lacks glucose-6-phosphatase → glucose-6-P goes to glycolysis; responds to epinephrine (no glucagon receptors).

Reciprocal Covalent Control of Glycogen

Phosphorylation: phosphorylase ON, synthase OFF (glucagon/epinephrine); Dephosphorylation by PP1: synthase ON, phosphorylase OFF (insulin).

Glucagon/Epinephrine Signaling Cascade

Hormone → G protein → adenylate cyclase → cAMP → PKA → phosphorylase kinase → glycogen phosphorylase (and PKA phosphorylates synthase → OFF).

Muscle Glycogen Breakdown Local Signals

Ca²⁺ (contraction) activates phosphorylase kinase; AMP activates phosphorylase directly; ATP and G6P inhibit.

von Gierke Disease (GSD I)

Glucose-6-phosphatase deficiency in liver; severe fasting hypoglycemia, enlarged liver, lactic acidosis; treat after meals, never fasting.

Pompe Disease (GSD II)

Lysosomal α-glucosidase deficiency; all tissues; enlarged heart, muscle weakness.

McArdle Disease (GSD V)

Muscle glycogen phosphorylase deficiency; exercise intolerance, cramps, myoglobinuria; normal blood glucose (liver glycogen normal).