10.1 Carbohydrates

Chemistry is Session 2, and carbohydrates open the domain

Chemistry is 13% of NBCE Part I and is tested in Session 2 with Pathology and Microbiology. Inside Chemistry, Carbohydrates are 13%. The official test plan asks for catabolic and anabolic pathways, structure/properties/function, and nutritional concepts (food sources and digestion). Citric acid cycle and the electron-transport chain are Biochemical Energetics in the next chapter; stop this section at pyruvate and the NADPH/ribose branches that actually belong to carbohydrate metabolism.

/practice/nbce-part1Practice questions with detailed explanations

Quick Answer: Glucose is a D-aldohexose stored as glycogen (α-1,4 chains, α-1,6 branches). PFK-1 is the committed glycolytic step (AMP and fructose-2,6-bisphosphate on; ATP and citrate off). Gluconeogenesis uses pyruvate carboxylase, PEPCK, fructose-1,6-bisphosphatase, and glucose-6-phosphatase. PPP NADPH protects red cells. SGLT1/GLUT5/GLUT2 handle absorption.

Structure, stereochemistry, and glycosidic bonds

A monosaccharide is a polyhydroxy aldehyde (aldose) or ketone (ketose). Glucose is an aldohexose; fructose is a ketohexose. Fischer projection D/L is set by the chiral carbon farthest from the carbonyl: almost all mammalian sugars are D. Epimers differ at one chiral carbon (glucose/galactose at C4; glucose/mannose at C2). Anomers differ at the carbonyl carbon after ring closure: α versus β. In solution, glucose mutarotates through the open chain to an equilibrium mixture (~36% α, ~64% β).

Haworth rings: glucose usually a pyranose (six-membered); fructose in sucrose is a furanose (five-membered). The anomeric carbon is the only carbon bonded to two oxygens. If that OH is free, the sugar is reducing (can open and reduce a cupric reagent). If the anomeric carbons of both partners are locked in a glycosidic bond, the disaccharide is nonreducing.

Glycosaminoglycans (GAGs) are repeating disaccharides, usually a uronic acid plus an amino sugar, often sulfated. Aggrecan in the intervertebral disc nucleus pulposus carries chondroitin sulfate and keratan sulfate. The polyanion holds water; that is carbohydrate function, not a Part II disc-herniation lecture. Glycoproteins (N-linked on Asn, O-linked on Ser/Thr) and glycolipids decorate membranes; blood-group antigens are oligosaccharides on red-cell glycolipids and glycoproteins.

Worked stereochemistry item. Galactose is the C4 epimer of glucose. UDP-galactose 4-epimerase (GALE) interconverts UDP-Glc and UDP-Gal so dietary galactose can enter glucose pathways and so glycoprotein synthesis can proceed when lactose is not on the plate.

Digestion, food sources, and absorption

Dietary carbohydrate in a mixed human diet is mostly starch (amylose and amylopectin), sucrose, lactose, and smaller amounts of fructose, glucose, and poorly digested fiber (cellulose, some pectins). Salivary α-amylase (ptyalin) and pancreatic α-amylase are endoglucosidases that attack internal α-1,4 bonds and spare α-1,6 branches and the terminal reducing end. Products are maltose, maltotriose, and α-limit dextrins.

Brush-border oligosaccharidases finish the job: maltase-glucoamylase, sucrase-isomaltase (sucrose plus α-1,6 branches), lactase, trehalase. Lactase declines after weaning in much of the world; undigested lactose draws water and is fermented to gas — osmotic diarrhea, not an allergy.

Ouabain-sensitive Na+/K+-ATPase on the basolateral membrane keeps intracellular sodium low so SGLT1 can run. Oral rehydration solution works because glucose-stimulated sodium (and water) absorption survives in many diarrheas.

Exam trap: insulin does not gate intestinal GLUT2/SGLT1 the way it gates muscle GLUT4. A fed person absorbs starch whether or not insulin has been injected. Insulin does move GLUT4 to the sarcolemma so muscle and fat can clear post-prandial glucose.

Glycolysis: ten steps, three irreversible, one committed

Glycolysis converts glucose to two pyruvate in the cytosol. Energy investment is 2 ATP (hexokinase/glucokinase and PFK-1). Payoff is 4 ATP (phosphoglycerate kinase and pyruvate kinase) plus 2 NADH (glyceraldehyde-3-phosphate dehydrogenase). Net: 2 ATP + 2 NADH per glucose. Anaerobic tissues (RBC always; exercising muscle) regenerate NAD+ by lactate dehydrogenase, so the net is 2 ATP and 2 lactate, no NADH leftover.

Phosphofructokinase-1 (PFK-1) is the enzyme to know cold. ATP occupancy of an allosteric site raises the K0.5 for fructose-6-phosphate and flattens the sigmoid. AMP reverses that. Citrate reports that the mitochondria are full and further glycolytic carbon is not needed. Fructose-2,6-bisphosphate is the most potent feed-forward activator in liver and the hormone-coupling device:

• The bifunctional enzyme PFK-2/FBPase-2 both makes and breaks F-2,6-BP.
• Insulin (fed liver): protein phosphatase dephosphorylates the liver bifunctional enzyme → PFK-2 on → F-2,6-BP rises → PFK-1 on → glycolysis.
• Glucagon (fasted liver): cAMP-PKA phosphorylates the bifunctional enzyme → FBPase-2 on → F-2,6-BP falls → PFK-1 off, and the same fall de-inhibits fructose-1,6-bisphosphatase so gluconeogenesis can run.
• Muscle PFK-2 is a different isoform and is not turned off by glucagon/PKA the same way — muscle is not in the business of exporting glucose.

Pyruvate fates (do not dump the whole TCA map here): aerobic tissues send pyruvate into mitochondria via pyruvate dehydrogenase (TPP, lipoamide, CoA, FAD, NAD+) to acetyl-CoA. PDH is inactivated by phosphorylation (PDH kinase, stimulated by acetyl-CoA, NADH, ATP) and reactivated by PDH phosphatase (stimulated by insulin and Ca2+). Cytosolic pyruvate can also transaminate to alanine (Cahill cycle) or be reduced to lactate (Cori cycle).

2,3-bisphosphoglycerate (2,3-BPG) in red cells is a glycolytic shunt (Rapoport-Luebering) that lowers hemoglobin O2 affinity. That is why a glycolysis-block in RBCs can present as both hemolysis and a change in the oxygen curve — chemistry meeting respiratory physiology.

Gluconeogenesis: four bypasses, not a simple reverse

Liver (and to a lesser extent kidney cortex) can make free glucose. Muscle cannot, because it lacks glucose-6-phosphatase. Reversing glycolysis is thermodynamically illegal at the three kinase steps, so gluconeogenesis uses four enzymes:

1. Pyruvate carboxylase (mitochondrial, biotin, acetyl-CoA is an obligate allosteric activator) carboxylates pyruvate to oxaloacetate. No acetyl-CoA, no gluconeogenesis — a starved liver that cannot β-oxidize (carnitine defect, CPT-I defect) becomes hypoglycemic.
2. PEPCK decarboxylates and phosphorylates oxaloacetate to PEP (GTP). Cytosolic PEPCK is glucagon/cortisol-induced and insulin-repressed.
3. Fructose-1,6-bisphosphatase hydrolyzes F-1,6-BP. Inhibited by AMP and by F-2,6-BP — the mirror of PFK-1.
4. Glucose-6-phosphatase (endoplasmic reticulum of liver and kidney; glucose-6-phosphate translocase plus catalytic subunit) releases free glucose into blood.

Carbon sources: lactate (Cori), glucogenic amino acids (especially alanine), glycerol from lipolysis (enters at DHAP via glycerol kinase — liver has it, adipose does not), and propionyl-CoA from odd-chain fatty acids. Acetyl-CoA from even-chain fat cannot make net glucose in humans: the two carbons that enter citrate leave as CO2 in the isocitrate dehydrogenase and α-ketoglutarate dehydrogenase reactions.

Energy cost: 6 ATP equivalents per glucose from 2 pyruvate (pyruvate carboxylase 2 ATP, PEPCK 2 GTP, 3-phosphoglycerate kinase 2 ATP). That is why gluconeogenesis is a fasting, glucagon/cortisol, fatty-acid-oxidation-supported pathway.

Glycogen: synthesis, phosphorolysis, and the classic storage diseases

Glycogenesis. Glucose-6-phosphate → glucose-1-phosphate (phosphoglucomutase) → UDP-glucose (UDP-glucose pyrophosphorylase; pyrophosphate hydrolysis pulls). Glycogen synthase adds UDP-glucose to a nonreducing end with α-1,4 bonds; it needs a glycogenin primer. Branching enzyme (amylo-α-(1,4)→α-(1,6)-transglycosylase) moves a ~6–8 residue oligosaccharide to a C6-OH, creating a branch. Branches raise solubility and the number of nonreducing ends.

Glycogenolysis. Glycogen phosphorylase (pyridoxal phosphate) phosphorolyzes α-1,4 bonds to glucose-1-phosphate until four residues from a branch. Debranching enzyme has two activities: 4:4 transferase (moves the outer three glucoses) and 1,6-glucosidase (releases the branch-point glucose as free glucose, not G1P). Liver G6Pase then exports glucose. Muscle phosphorylase feeds glycolysis locally.

Hormone cascade you will see again in the enzyme section: glucagon (liver) or epinephrine (liver and muscle) → cAMP → PKA → phosphorylase kinase → phosphorylase a (active). The same PKA phosphorylates glycogen synthase to the inactive form. Insulin activates protein phosphatase-1, reversing both. Muscle phosphorylase is also opened by AMP and by Ca2+-calmodulin on phosphorylase kinase during contraction — so a contracting muscle dumps glycogen without waiting for a hormone.

Pentose phosphate pathway, fructose, and galactose

Oxidative PPP (cytosol): glucose-6-phosphate dehydrogenase (G6PD, NADP+) → 6-phosphogluconolactone → 6-phosphogluconate dehydrogenase → ribulose-5-phosphate + CO2. Net per glucose-6-phosphate through both dehydrogenases: 2 NADPH + 1 CO2. NADPH is the reductant for fatty-acid and cholesterol synthesis and for glutathione reductase. RBCs have no other NADPH source; G6PD deficiency (X-linked) presents as hemolysis after primaquine, sulfa drugs, dapsone, infection, or fava beans. Heinz bodies and bite cells are the smear vocabulary.

Nonoxidative PPP: transketolase (thiamine pyrophosphate) and transaldolase shuffle 3–7 carbon sugars so the cell can make ribose-5-phosphate for nucleotides without NADPH, or make extra NADPH without ribose (recycle to F6P and GAP and re-enter glycolysis/gluconeogenesis). A transketolase assay with and without TPP is an old functional test of thiamine status.

Fructose. Hepatic fructokinase phosphorylates fructose to fructose-1-phosphate. Aldolase B splits F1P to DHAP and glyceraldehyde. That bypasses PFK-1, so a large fructose load can dump triose phosphates into liver and raise lipogenesis. Essential fructosuria (fructokinase) is benign — fructose spills in urine. Hereditary fructose intolerance (aldolase B) traps F1P, sequesters phosphate, stops glycogenolysis and gluconeogenesis, and causes hypoglycemia, liver injury, and aversion to sweets after weaning.

Galactose. Galactokinase → Gal-1-P. GALT (galactose-1-phosphate uridyltransferase) trades with UDP-glucose to make UDP-galactose + G1P. GALE epimerizes UDP-Gal/UDP-Glc. Classic galactosemia (GALT) : feeding a neonate milk produces liver failure, E. coli sepsis risk, cataracts (galactitol via aldose reductase), and Fanconi-type renal wasting. Galactokinase deficiency is mainly cataracts. Remove lactose; soy formulas are the practical move.

Ethanol is not a carbohydrate, but it wrecks carbohydrate numbers: alcohol dehydrogenase and aldehyde dehydrogenase generate NADH. High NADH drives oxaloacetate toward malate (starving gluconeogenesis), pyruvate toward lactate, and DHAP toward glycerol-3-phosphate (fatty liver). Fasting plus binge drinking → hypoglycemia and lactic acidosis. That item is carbohydrate regulation, not a bar-exam fact.

/practice/nbce-part1Practice questions with detailed explanations