L25 - Making And Breaking Biological Molecules
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What is the importance of chemistry in biology? (6)
• generate energy and transfer into useful form (ATP, ion, metabolite grads) • partition molecules into dif compartments • catalyse reaction - occur on a meaningful timescale • maintain molecular structure • regulate activity of other molecules • transmit and store info
What does some of this chemistry rely on? (2)
• making and breaking of covalent bonds (catalysis, energy gen in ATP, storage of info) • weak forces stabilising protein 3 struc (molecular structure, ion/metabolite grad)
What type of chemistry is it when protein kinase catalyses the transfer of a phosphate group from ATP to a threonine residue?
Covalent chemistry
What type of chemistry is it when negatively charged DNA is tightly wrapped around positively charged histone proteins enabling effective packaging in the nucles of the cell?
Non-covalent chemistry
What does the specificity of molecular interactions rely on? (3)
• molecular shape • chemical complementarity • spatiotemporal overlap
How does molecular shape affect specificity in molecular interactions?
Different molecules fitting togehter like a 3D jigsaw
How does chemical complementarity affect specificity in molecular interactions?
+ve charges interacting with -ve charges - hydrogen bonding potential fulfilled - cluters of hydrophobic moieties
How does spatiotemporal overlap affect specificity in molecular interactions?
Molecules being in the same place at the same time
Where do interactions occur?
Protein surface or in active site
What are B-lactam antibiotics?
Most prescribed antibiotic class - penicillins, cephalosporins, carbapenems, monobactams
What do B-lactam antibiotics target?
enzymes known as penicillin-binding proteins (PBPs)
What are PBPs involved in?
Biosynthesis of the cell wall of gram-negative bacteria - irreversibly inhibited by B-lactam antibiotics
Where are B-lactamases found in?
Gram-negative bacteria
What do B-lactamases hydrolyse?
Amide bond of the four-membered B-lactam ring in many antibiotics - can no longer bind to target = loss of activity
What happens if an antibiotic has no activity in its target bacteria?
Bacteria is resistant to the antibiotic - B-lactam hydrolysis is a mechanism of antimicrobial resistance
What happens to the molecular shape of benzylpenicillin binding to PC1 B-lactamase from S.aureus? (3)
• penicillin binds in a pocket on surface of PC1 • fits well in its binding pocker • bound drug displaces so binding site visible
What are interactions in chemical complementarity of benzylpenicillin binding to PC1 B-lactamase form S.aureus? (5)
• Hydrogen bonding to Gln237 backbone • Hydrogen bonds to solvent (water) • Hydrogen bond to Asn132 side chain • Hydrophobic residues around benzene ring • ring stacking between benzine ring and Tyr105 sidechain
Comparing B-lactamase binding pocket with that in a PBP? (2)
• both pockets form H bonds to same chem groups • PBP forms covalent bonds to sidechain of Ser434 = acyl-enzyme
What happens to the mutant PBP enzyme which Asn489 mutated to Asp?
Mutation leads to a reduction of number of H bonds/interactions - bind more weakly
What is the covalent chemistry in B-lactam hydrolysis? (6)
• deprotenated serine acts as nucleophil to B-lactam • hydrolysis of covalent bond between C-N with OSer • reaction stops in PCP enzyme (Acyl-enzyme covalently inhibited) • H in H2O protenated • OH to C=O • LG of OSer = hydrolysed B-lactam • H-O-Ser regenated
What makes it difficult to design new antibiotics?
Similar interactions in both target and off-target enzymes