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BI5.1-9 | Chemistry & Metabolism of Proteins and Immunology — Part 1

Amino Acid Structure — The Universal Building Block (BI5.1)

Every amino acid has the same core structure — a central alpha-carbon (C-alpha) bonded to four groups:

Figure: Amino Acid Structure — The Universal Building Block (BI5.1)

1. An amino group (-NH2) — the nitrogen-containing end
2. A carboxyl group (-COOH) — the acid end
3. A hydrogen atom (-H)
4. A side chain (R group) — this is the variable part that makes each amino acid unique

At physiological pH (7.4), amino acids exist as zwitterions — the amino group is protonated (-NH3+) and the carboxyl group is deprotonated (-COO-). This means amino acids carry both a positive and negative charge simultaneously.

All amino acids except glycine are optically active — they have a chiral centre at the alpha-carbon. Human proteins use only L-amino acids (the D-form is found in bacterial cell walls — this is why D-amino acids are targets for antibiotics).

Classification by nutritional significance:

• Essential amino acids (9) — your body cannot synthesise them; they must come from diet: PVT TIM HALL (Phe, Val, Trp, Thr, Ile, Met, His, Arg, Leu, Lys). Arg is semi-essential — needed in children for growth.



Figure: Classification by nutritional significance:

• Non-essential amino acids (11) — your body can make them from metabolic intermediates.

Classification by R-group chemistry:

• Non-polar/hydrophobic — Gly, Ala, Val, Leu, Ile, Pro, Phe, Trp, Met (these tend to cluster inside proteins, away from water)



Figure: Classification by R-group chemistry:

• Polar uncharged — Ser, Thr, Cys, Tyr, Asn, Gln (can form hydrogen bonds)
• Positively charged (basic) — Lys, Arg, His (attracted to negative charges)
• Negatively charged (acidic) — Asp, Glu (attracted to positive charges)

Why does classification matter clinically? Because phenylketonuria (PKU) is the inability to convert phenylalanine (essential) to tyrosine (non-essential). If Phe accumulates, it damages the brain. If you understand the classification, you understand why a Phe-restricted diet works — you're removing the amino acid the body can't process while supplementing the one it can't make from it.

Protein Structure — Four Levels of Organisation (BI5.2)

Amino acids join together through peptide bonds — a covalent bond formed between the carboxyl group of one amino acid and the amino group of the next, releasing water (condensation reaction). Two amino acids make a dipeptide, three make a tripeptide, and chains longer than 10 are polypeptides. A protein is one or more polypeptide chains folded into a specific 3D shape.

Figure: Protein Structure — Four Levels of Organisation (BI5.2)

Proteins have four levels of structure, and each level matters clinically:

1. Primary structure — the linear sequence of amino acids, read from the N-terminus (amino end) to the C-terminus (carboxyl end). This sequence is encoded by DNA. A single amino acid change here can cause disease — in sickle cell disease, glutamic acid at position 6 of the beta-globin chain is replaced by valine (Glu→Val). That's one amino acid out of 146, and it transforms the behaviour of the entire molecule.

2. Secondary structure — local folding patterns stabilised by hydrogen bonds between backbone atoms (not R-groups):
- Alpha-helix (α-helix) — the polypeptide coils into a right-handed spiral. Each turn has 3.6 amino acids. Think of it as a spiral staircase. Keratin (hair, nails) is largely alpha-helical.
- Beta-sheet (β-sheet) — the chain folds back and forth in a zigzag, forming flat sheets held together by hydrogen bonds between parallel or antiparallel strands. Silk fibroin is mostly beta-sheet.

3. Tertiary structure — the overall 3D shape of a single polypeptide, determined by interactions between R-groups:
- Hydrophobic interactions (non-polar R-groups cluster inside, away from water)
- Hydrogen bonds (between polar R-groups)
- Ionic bonds (between oppositely charged R-groups)
- Disulfide bonds (covalent S-S links between two cysteine residues — these are the strongest)

This is the level where the protein becomes functional. Myoglobin (an oxygen-carrying protein in muscle) is a single polypeptide with a specific tertiary structure.

4. Quaternary structure — the arrangement of multiple polypeptide subunits into a functional complex. Haemoglobin is the classic example: it has 4 subunits (2 alpha + 2 beta chains). The quaternary structure allows cooperativity — when one subunit binds oxygen, the others change shape and bind oxygen more easily (this is why haemoglobin's oxygen dissociation curve is sigmoidal, not hyperbolic like myoglobin's).

Denaturation — when a protein loses its 3D structure (secondary, tertiary, quaternary) but keeps its primary sequence intact. Causes include heat, extreme pH, organic solvents, and heavy metals. A boiled egg is denatured egg white (albumin) — the proteins unfold irreversibly. Clinically, fever can denature enzymes if body temperature exceeds 41°C, which is why hyperthermia is a medical emergency.

Protein Classification and Functions (BI5.2 continued)

Proteins are classified in several ways:

Figure: Protein Classification and Functions (BI5.2 continued)

By shape:
- Fibrous proteins — long, rope-like, insoluble in water, structural roles. Examples: collagen (bones, tendons, skin — most abundant protein in the body, ~30% of total protein), keratin (hair, nails), elastin (blood vessel walls, lungs).
- Globular proteins — compact, spherical, soluble in water, functional roles. Examples: haemoglobin (oxygen transport), albumin (plasma oncotic pressure), enzymes (catalysis), antibodies (immunity).

By composition:
- Simple proteins — only amino acids. Example: albumin.
- Conjugated proteins — amino acids + a non-protein component (prosthetic group):
- Glycoproteins (+ carbohydrate) — e.g., mucins, antibodies
- Lipoproteins (+ lipid) — e.g., LDL, HDL
- Metalloproteins (+ metal ion) — e.g., ferritin (iron), ceruloplasmin (copper)
- Chromoproteins (+ coloured prosthetic group) — e.g., haemoglobin (haem), cytochromes
- Nucleoproteins (+ nucleic acid) — e.g., histones
- Phosphoproteins (+ phosphate) — e.g., casein (milk)

Collagen — the protein you'll meet in every organ:
Collagen has a unique structure — three polypeptide chains (alpha chains) wound around each other in a triple helix (like a rope). Every third amino acid is glycine (Gly-X-Y repeat, where X is often proline and Y is often hydroxyproline). Vitamin C is essential for the hydroxylation of proline and lysine in collagen — without it, collagen is weak, and you get scurvy (bleeding gums, poor wound healing, loose teeth).

There are at least 28 types of collagen. The clinically important ones:
- Type I — bone, skin, tendon, dentin (90% of body collagen)
- Type II — cartilage, vitreous humour
- Type III — blood vessels, skin, uterus (reticular fibres)
- Type IV — basement membranes (forms a mesh, not fibres)

Spiral forward: In Anatomy, you're learning about bones and cartilage. Type I collagen is why bone is strong in tension (mineral gives compressive strength, collagen gives tensile strength). In Pathology, you'll learn about osteogenesis imperfecta — a genetic defect in Type I collagen that makes bones brittle.

Protein Digestion and Absorption (BI5.3)

When you eat a piece of chicken, the proteins in it must be broken down into individual amino acids (or di/tripeptides) before your intestine can absorb them. This happens in three stages:

Figure: Protein Digestion and Absorption (BI5.3)

1. Stomach (pH 1.5–2.5):
- Pepsinogen (secreted by chief cells) is activated to pepsin by hydrochloric acid (HCl from parietal cells)
- Pepsin is an endopeptidase — it cuts proteins within the chain, preferring bonds next to aromatic amino acids (Phe, Tyr, Trp)
- The acidic pH also denatures proteins, unfolding them so enzymes can access the peptide bonds

2. Small intestine (pH 7–8):
Pancreatic enzymes take over (all secreted as inactive zymogens to prevent self-digestion):
- Trypsinogen → trypsin (activated by enterokinase from duodenal mucosa) — this is the master activator
- Trypsin then activates chymotrypsinogen → chymotrypsin, proelastase → elastase, and procarboxypeptidase → carboxypeptidase
- Trypsin, chymotrypsin, and elastase are endopeptidases (cut within the chain)
- Carboxypeptidase is an exopeptidase (chops amino acids from the C-terminus)

3. Brush border (intestinal mucosa):
- Aminopeptidases (exopeptidases — chop from the N-terminus) and dipeptidases complete the breakdown
- Final products: free amino acids, dipeptides, and tripeptides

Absorption:
- Free amino acids are absorbed by sodium-dependent active transport (secondary active transport using the Na+ gradient) — similar to glucose absorption
- Di- and tripeptides are absorbed by the PepT1 transporter (H+-dependent) and then hydrolysed inside the enterocyte
- Absorbed amino acids enter the portal blood and travel to the liver — the body's amino acid processing centre

Clinical pearl: Hartnup disease is a defect in the neutral amino acid transporter in the intestine and kidney. Tryptophan (the precursor of niacin) is poorly absorbed, leading to pellagra-like symptoms: dermatitis, diarrhoea, and dementia.