med chem iv
TRANSCRIPT
Medicinal Chemistry IV Enzyme Structure and Function
Enzyme as Catalyst
How do enzyme catalyze reactions ?
Active site of Enzyme
Isozyme
Enzyme kinetics
Enzyme as Catalyst
Niacin
Nicotinamide adenine dinucleotide (NAD)
Enzyme as Catalyst : Activation Energy
Where E is the activation energy and A is the frequencyfactor.
How do enzymes catalyzed reactions ?
Enzymes provide a reaction surface and a suitable environment.
Enzymes bring reactants together and position them correctly so that they easily attain their transition state configurations.
Enzymes weaken bonds in the reactants.
Enzymes may participate in the reaction mechanism.
Enzymes form stronger interactions with the transition state than with the substrate or the product.
The process of enzyme catalysis
The active site of an enzyme
Binding - amino acid residue is involved in binding the substrate or a cofactor to The active site;
Amino acids present in the active site can have one of two roles:
Catalytic- Amino acids present in the active site can have one of two roles:
Substrate binding at an active site
The interactions which bind substrates to the active sites of enzymes ?
pyruvic acid - substrate for lactate dehydrogenas
The catalytic role of enzymes
Mechanism of Enzyme catalysis
Binding interactions
Acid/Base catalysis
Nucleophilic groups
Cofactors
Binding interactions
Not only enzyme but substrate to change its shape…..
Enzyme stabilizes transition state more than substrate…..
e.g. Pyruvic acid interact with active site of lactate dehydrogenase viaH bond, ionic bond and one van der Waals interactions
Fischer’s lock and key hypothesis
Koshland’s theory of induced fit
Acid/base catalysis
Acid/base catalysis is often provided by the amino acid histidine, which contains an imidazole ring as part of its side chain.
3-hydroxy-3-methyl-glutaryl-CoA reductase HMGR
NH3
O
HO
O
O
L-glutamic acid
17β-Hydroxysteroid dehydrogenases
Tyrosine
Nucleophilic groups
The amino acids serine and cysteine are present in the active sites of some enzymes. These amino acids havenucleophilic residues (OH and SH respectively) which are able to participate in the reaction mechanism.
Hydrolysis of peptide bonds catalyzed by the enzyme chymotrypsin.
Cofactors
Many enzymes require additional non-protein substances called cofactors for The reaction to take place.
Prosthetic groups
A knowledge of how the coenzyme binds to the active site allows the possibility of designing enzyme inhibitors that will fit the same region
SN+
NH2
NN
Cl-PO
O OHOH
OPO
OH
THIAMINE PYROPHOSPHATE
N
OH
O
PO
OOH
OH
PYRIDOXALPHOSPHAT
HS
HN
HN
HO
OP O
P O
OPHO
HOO
OH
NN
N N
NH2
O
OH
O
OH
O
OO
COENZYME A
OH
NHO
HHN
H S
O
Biotin
Naming and classifi cation of enzymes
The name of an enzyme reflects the type of reaction it catalyzes, and has the suffix -ase to indicate that it is an enzyme. For example, an oxidase enzyme catalyzes an oxidation reaction.
Regulation of enzymes/ allosteic binding
Enzymes are controlled by agents which caneither enhance or inhibit catalytic activity
Regulation of enzymes/External
Phosphorylation
Epinephrine, also known as adrenaline, is a medication, hormone and neurotransmitter.
Regulation of enzymes/External
Cyclic adenosine monophosphate
adenylate cyclase adenylate cyclase
Regulation of enzymes/External
Isozymes
Enzymes having a quaternary structure are made up of a number of polypeptide subunits. The combination of these subunits can differ in different tissues. Such variations are called isozymes . For example, there are five different isozymes of mammalian lactate dehydrogenase (LDH) tetrameric enzyme made up of four polypeptide subunits.
HHHH, HHHM, HHMM, HMMM, and MMMM
Points to remember
Enzymes are proteins that act as the body’s catalysts by binding substrates and participating in the reaction mechanism.
The active site of an enzyme is usually a hollow or cleft in the protein. There are important amino acids present in the active site that either bind substrates or participate in the reaction mechanism
Binding of substrate to an active site involves intermolecular bonds.
The amino acid histidine is often present in active sites and acts as an acid/base catalyst. Glutamic acid, aspartic acid, and tyrosine also act as acid/base catalysts in some enzymes
Cofactors are metal ions or small organic molecules (coenzymes) which are required by many enzymes. Coenzymes can be viewed as the body’s chemical reagents