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Lecture notes Year 1 MBChB: Introduction to Medical Sciences (IMS) £7.49   Add to cart

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Lecture notes Year 1 MBChB: Introduction to Medical Sciences (IMS)

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Concise lecture notes from the enzymes strand of the IMS module taught in the first year of the MBChB course at the University of Leeds!

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  • January 2, 2021
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  • 2017/2018
  • Lecture notes
  • Mbchb year 1: introduction to medical science
  • All classes
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ENZYMES

INTRODUCTION TO ENZYMES


Relevance of enzymology to medicine
 Drug action, biochemical defects in enzymes underlie disease, clinical diagnosis/prognosis
 Many drugs are enzyme inhibitors, e.g. codeine

How do enzymes decrease the activation energy of a reaction
 By providing catalytically competent groups (e.g. metal ions) for a specific reaction mechanism
 By binding substrates such that their orientation is optimized for the reaction
 By preferentially binding and stabilising transition states of the substrate
 Increase the rate at which the reaction equilibrium is reached, but do not shift the position of equilibrium

Active site
 ESC  EPC takes place
 It’s a 3D entity comprising crucial amino acid residue
 Binds substrate via multiple weak interactions
 Provides specificity because of its unique conformation of atoms

Assay: A procedure for measuring the biochemical or immunological activity of a sample

Enzyme kinetics
 k1 is the rate of formation of enzyme-substrate complex
 k2 and k3 are the rates of dissociation of ES complex
 Km: substrate conc at which the rate is half Vmax ; a low Km indicates high affinity of the enzyme for its substrate- low
conc of substrate required to saturate enzyme

The Michaelis-Menten Equation
 Km will always be the same




pH
Temperatur
e




Irreversible
inhibition
 Covalent modification of amino acid side chains in the active site
 E.g. carboxymethylation of cysteine side chains by idoacetamide and snake venom for acetylcholinesterase

Reversible inhibition
Competitive Non-competitive
 Enzyme can bind substrate OR inhibitor, but not both  Inhibitor and substrate can bind simultaneously
at the same time  Binding occurs at independent sites
 Substrate and inhibitor compete for active site  Inhibitor alters conformation or accessibility of active
 Substrate and inhibitor often share similar structures site.
 Pharmacologically important  Inhibition not affected by high substrate concentration
 Inhibition overcome by high substrate concentration

, Aspirin: Covalent modification of a serine residue in the active site. Competitive, IRREVERSIBLE
Ibuprofen: Binds to active site, but not covalently attached. Competitive, REVERSIBLE

Cofactors
 Metal ions provided as trace elements in the diet
 Essential components in active sites in some enzymes
 Cu2+, Zn2+, Fe3+, Mn2+, even Mo4+, occur naturally
 Metal ion may bind reactants electrostatically, or may act as oxidising agents
 Other metal ions (e.g. Mg2+, Ca2+) may be required for activity, but are not part of
active site.

REGULATION OF ENZYME ACTIVITY


Coenzymes
 E.g. water soluble vitamins
 They function as carriers of reaction components
o NADH and FADH2 carry electrons (‘reducing power’)
o Coenzyme A carries acyl units
o Biotin and thiamine pyrophosphate carry CO2 units (bound to
carboxylases)
o PO3 group gives specificity between NADP and NAD

Glucose- 6-Phosphate dehydrogenase - most commonest enzyme deficiency
 X-linked recessive, most carriers asymptomatic
 The enzyme produces a large proportion of the body’s NADPH needed to
drive biosynthesis of nucleic acids, lipids etc.
 Where symptomatic, can include haemolytic crises, jaundice (can lead to
brain damage (kernicterus) in infants)
 Crises can be triggered by certain drugs, foods or infections
 G6PDH mutations can effect either the stability of the dimeric enzyme, the
binding of the regulatory NADP+ cofactor, or the structure of the active site
itself
 Extra glucose goes into PPP – pentose phostphate pathway

Why do we need NADPH?
 NADPH is very important in maintaining the levels of reduced glutathione in cells
 Glutathione keeps cell membranes happy, by reducing lipid hydroperoxides
 If they are not removed, the hydroperoxides react to cause cleavage of the acyl chains and ultimately red cell lysis.
Glutathione reduces them to alcohols by glutathione peroxidase
 The resultant GSSG is reduced back to GSH by NADPH, catalysed by glutathione reductase
 Anti-malarial primaquine can trigger a haemolytic crisis; it stimulates peroxide formation thereby increasing the
demand for NADPH to a level that the mutant enzyme cannot provide

Thiopurine methyl transferase (TPMT)
 Thiopurine drugs are used as anti-cancer agents
 Can be incorporated into DNA during replication in actively growing cells, but
then block further extension of the DNA chain; growth is arrested
 Because cancer cells have a particularly high demand for new DNA chains
(because they grow more rapidly than most other cells), these cytotoxic drugs will
tend to kill cancer cells more effectively than (most) other cells in the body

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