Role of Metal Ions in Biological Systems

Level: Undergraduate (UG) | Postgraduate (PG) | Competitive Exams (CSIR-NET, GATE, IIT-JAM, NEET)

Key Learning Objectives:

• Understand structural, catalytic, and signaling roles of metal ions
• Correlate coordination chemistry with biofunction
• Identify deficiency diseases and therapeutic roles
• Link metal ions to enzyme active sites and electron transfer

Metal ions are indispensable in biological systems, acting as cofactors, structural components, signaling molecules, and catalysts in enzymatic reactions. Approximately one-third of all proteins require metal ions for proper function. These ions include both essential trace elements (e.g., Fe, Zn, Cu, Mn) and alkali/alkaline earth metals (e.g., Na⁺, K⁺, Mg²⁺, Ca²⁺).

Classification of Metal Ions in Biology

Category	Examples	Primary Roles
Alkali Metals	Na⁺, K⁺	Membrane potential, nerve impulse transmission, osmotic balance
Alkaline Earth Metals	Mg²⁺, Ca²⁺	Enzyme activation, muscle contraction, second messengers
Transition Metals	Fe, Cu, Zn, Mn, Co, Mo	Redox reactions, oxygen transport, enzyme catalysis

1. Sodium (Na⁺) and Potassium (K⁺)

1.1 Biological Role

• Electrolyte balance: Maintain osmotic pressure, fluid balance
• Nerve impulse transmission: Action potential via Na⁺/K⁺ gradient
• Muscle contraction: Depolarization triggers Ca²⁺ release
• Nutrient uptake: Na⁺-glucose symport, Na⁺/K⁺-ATPase pump

1.2 Na⁺/K⁺-ATPase (Sodium-Potassium Pump)

Structure: α₂β₂ tetramer; α-subunit has 10 TM helices, ATP & ouabain binding sites

Mechanism (Post-Albers Cycle):

1. E1 (open cytosol): 3 Na⁺ bind → ATP → phospho-E1 → E2-P (open extracellular)
2. 2 K⁺ bind → dephosphorylation → E1 + 2 K⁺ released inside

Stoichiometry: 3 Na⁺ out : 2 K⁺ in : 1 ATP hydrolyzed

Exam Hotspot: Ouabain/cardiac glycosides inhibit Na⁺/K⁺-ATPase → ↑ intracellular Na⁺ → ↑ Ca²⁺ → stronger heart contraction (digitalis action)

1.3 Deficiency & Excess

Ion	Deficiency	Excess
Na⁺	Hyponatremia, muscle cramps	Hypertension, edema
K⁺	Hypokalemia, arrhythmia	Hyperkalemia, cardiac arrest

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2. Calcium (Ca²⁺)

2.1 Structural Role

• Bone & teeth: Hydroxyapatite [Ca₁₀(PO₄)₆(OH)₂]
• Exoskeletons (crustaceans): CaCO₃

2.2 Signaling Role (Second Messenger)

• Muscle contraction: Binds troponin-C → conformational change → actin-myosin interaction
• Neurotransmission: Triggers vesicle fusion (synaptotagmin)
• Blood clotting: Factor IV in cascade; γ-carboxyglutamate (Gla) in prothrombin binds Ca²⁺

2.3 Key Proteins

Protein	Ca²⁺ Binding Site	Function
Calmodulin (CaM)	4 EF-hand motifs	Activates CaM-kinase, MLCK
Troponin-C	2 high-affinity, 2 low-affinity sites	Muscle contraction
Calbindin	EF-hand	Intestinal Ca²⁺ absorption

MCQ Alert: EF-hand motif = helix-loop-helix; binds Ca²⁺ with pentagonal bipyramidal geometry

2.4 Regulation

• Parathyroid hormone (PTH): ↑ bone resorption
• Vitamin D (calcitriol): ↑ intestinal absorption
• Calcitonin: ↓ blood Ca²⁺

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3. Magnesium (Mg²⁺)

3.1 Role in Enzymes

• ATP-dependent reactions: Mg²⁺-ATP²⁻ complex (true substrate)
• Kinases: Hexokinase, PFK, creatine kinase
• DNA/RNA polymerases: Stabilizes pyrophosphate leaving group

3.2 Structural Role

• Chlorophyll: Mg²⁺ in porphyrin ring → light absorption
• Ribosomes: Stabilizes rRNA structure

Chlorophyll a: Mg²⁺ coordinated to 4 N atoms of porphyrin; 5th ligand = H₂O or protein His

PG Level: Mg²⁺ reduces ΔG‡ in phosphoryl transfer by charge shielding and orienting ATP γ-phosphate

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4. Iron (Fe)

4.1 Oxidation States

• Fe²⁺ (ferrous): Reduced form
• Fe³⁺ (ferric): Oxidized form

4.2 Oxygen Transport & Storage

Protein	Role	Coordination
Hemoglobin (Hb)	O₂ transport	Fe²⁺ in heme; 4N (porphyrin) + His (proximal) + O₂/H₂O (distal)
Myoglobin (Mb)	O₂ storage	Similar; higher O₂ affinity (P₅₀ = 2.8 torr vs 26 torr for Hb)

4.3 Electron Transfer

• Cytochromes: Fe³⁺/Fe²⁺ redox (E⁰' ≈ +0.3 V)
• Iron-Sulfur Proteins: [Fe₂S₂], [Fe₃S₄], [Fe₄S₄] clusters
• Rieske center: [2Fe-2S] with His ligation

4.4 Enzymes

Enzyme	Type	Function
Catalase	Heme	2H₂O₂ → 2H₂O + O₂
Cytochrome P450	Heme	C–H hydroxylation (Fe⁴⁺=O intermediate)
Nitrogenase	FeMo-co	N₂ → NH₃ (with Mo)

Cooperativity in Hb: T-state (deoxy) → R-state (oxy); Bohr effect: ↓ pH → ↓ O₂ affinity

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5. Copper (Cu)

5.1 Redox States

• Cu⁺ (d¹⁰): Reduced, tetrahedral
• Cu²⁺ (d⁹): Oxidized, square planar/Jahn-Teller distorted

5.2 Types of Cu Centers

Type	Geometry	Example	Function
Type 1 (Blue)	Trigonal	Plastocyanin	e⁻ transfer (E⁰ ≈ +0.34 V)
Type 2 (Normal)	Sq. planar	Cu/Zn-SOD	Catalytic
Type 3 (Coupled binuclear)	—	Hemocyanin	O₂ binding
CuA	Binuclear	Cyt. c oxidase	e⁻ entry
CuB	Monomer	Cyt. c oxidase	O₂ reduction

5.3 Key Enzymes

• Superoxide dismutase (Cu/Zn-SOD): Cu²⁺ ⇌ Cu⁺ cycle; Zn²⁺ structural
• Cytochrome c oxidase: 4e⁻ reduction of O₂ → H₂O
• Lysyl oxidase: Crosslinks collagen/elastin

Entatic State: Protein constrains Cu geometry for fast redox (plastocyanin)

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6. Zinc (Zn²⁺)

6.1 Properties

• Only Zn²⁺ (d¹⁰): No redox role
• Lewis acid: Activates substrates
• Geometry: Tetrahedral (most), trigonal bipyramidal (few)

6.2 Roles

• Structural: Zinc fingers (Cys₂His₂, Cys₃His)
• Catalytic: Carbonic anhydrase, carboxypeptidase, alcohol dehydrogenase
• Regulatory: Gene expression, insulin storage

6.3 Carbonic Anhydrase (CA)

Active site: Zn²⁺ coordinated to 3 His + H₂O (pKₐ ≈ 7)

Mechanism:

1. Zn–OH⁻ + CO₂ → Zn–OCO₂H⁻
2. H₂O displaces HCO₃⁻ → Zn–OH₂
3. Buffer deprotonates → Zn–OH⁻

k_cat: ~10⁶ s⁻¹ (fastest enzyme)

NET/GATE: Zn²⁺ in insulin hexamer: 2 Zn²⁺ per hexamer, stabilizes storage form

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7. Molybdenum (Mo)

7.1 Biological Form

• Molybdopterin (Moco): Mo coordinated to dithiolene of pterin
• Oxidation states: Mo⁶⁺, Mo⁵⁺, Mo⁴⁺

7.2 Mo Enzymes (Molybdoenzymes)

Enzyme	Cofactor	Reaction
Xanthine oxidase	Mo + [Fe-S] + FAD	Xanthine → Uric acid
Sulfite oxidase	Mo + heme	SO₃²⁻ → SO₄²⁻
Nitrogenase	FeMo-co	N₂ + 8H⁺ + 8e⁻ → 2NH₃ + H₂

7.3 FeMo-Cofactor (Nitrogenase)

Structure: [MoFe₇S₉C-homocitrate]; Mo at terminal, interstitial C

Mechanism: Lowe-Thorneley cycle (E₀ to E₈ states); 8e⁻/8H⁺

PG/Research: Mo is the only 4d metal in biology; deficiency → esophageal cancer (nitrosamine link)

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Summary Table (Exam Revision)

Metal	Main Role	Key Example	Deficiency
Na⁺	Nerve impulse	Na⁺/K⁺-ATPase	Hyponatremia
K⁺	Membrane potential	Action potential	Arrhythmia
Ca²⁺	Signaling	Calmodulin	Osteoporosis
Mg²⁺	Enzyme cofactor	Chlorophyll	Hypomagnesemia
Fe	O₂ transport, e⁻ transfer	Hemoglobin	Anemia
Cu	Redox, O₂ chemistry	Cyt. c oxidase	Menkes disease
Zn²⁺	Catalytic, structural	Carbonic anhydrase	Growth retardation
Mo	Oxotransfer, N₂ fixation	Nitrogenase	Rare (esophageal Ca)

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MCQs for Practice

1. The metal ion in chlorophyll is:

1. Fe²⁺
2. Mg²⁺
3. Zn²⁺
4. Cu²⁺

2. Which enzyme uses Zn²⁺ to catalyze CO₂ hydration at 10⁶ s⁻¹?

1. Catalase
2. Carbonic anhydrase
3. Alcohol dehydrogenase
4. Hexokinase

3. The FeMo-cofactor is present in:

1. Hemoglobin
2. Nitrogenase
3. Cytochrome c
4. Myoglobin

4. Ouabain inhibits:

1. Ca²⁺-ATPase
2. Na⁺/K⁺-ATPase
3. H⁺/K⁺-ATPase
4. Mg²⁺ transporter

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References

1. Berg, Tymoczko, Stryer: Biochemistry, 8th Ed.
2. Lippard & Berg: Principles of Bioinorganic Chemistry
3. Shriver & Atkins: Inorganic Chemistry, 6th Ed.
4. CSIR-NET/JRF Previous Year Papers (Bioinorganic Section)