36 - Oxidoreductases Flashcards
MECHANISM
of Statin Inhibition of HMGR
HMGR-Statin Complex Crystal Structures showed:
Statins bind to the active site
STERICALLY PREVENT HMG-CoA substrate from binding
the substrate binding pocket is rearranged to accomodate statins
VVVVV
CONFORMATIONAL FLEXIBILITY
IDPs & IDRs
- *Intrinsically DISORDERED**
- *Regions / Proteins**
Persist in a HIGH-Energy State
&
Ensemble of INTER-CONVERTING conformations
- can NOT be crystallized = CONSTANLY MOVING*
- *CONTINUIM**
Aldehyde Dehydrogenase
Type of Enzyme // Drug // Treatment
OXIDOREDUCTASE
DISULFRAM
alcoholism
- *Drug that TARGETS a OXIDOREDUCTASE?**
- *Indication**
ATORVASTATIN = Lipitor
targets HMG-CoA Reductase
Indicated as an:
- *adjunct to diet** in primary hypercholesterolemia & mixed dyslipidemia for the purpose of
- reducing RISK of CV events*
LDL
low-density lipoprotein
Transports Cholesterol
TO THE CELLS
which can then build up PLAQUE –> ATHEROSCLEROSIS
Heart –> angina / heart attack
Brain –> strokes
Peripherals –> leg pain
Statin Structure
HMG-Like Moeity
is conserved in statins
HMG-Like moety can be a = Lactone Pro-Drug
–> hydrolyzed IN VIVO to active HYDROXY-ACID FORM
Share Rigid & hydroPHOBIC groups
that are covalently linked the HMG-like Moiety
Reaction catalyzed by HMG-CoA reductase
FOUR ELECTRON REDUCTION
(de-acylation) of
- *HMG-CoA** —–> Mevalonate + CoA
- *Thioester** —-> Alcohol
very complex mechanism w/ multiple chemical steps
rate determining step is still UNKNOWN
Cyclooxygenases = COX
Type of Enzyme // Drug // Treatment
Oxidoreductase
ASA / IBU / APAP
pain / fever / inflammation
How do Statins explore the
Conformational Flexibility of HMGR?
INDUCED FIT
Statins create a hydrophobic binding pocket near the active site
the binding causes the
HELIX to accomodate the statin
FLAP DOMAIN
of HMGR
when occupied by 0-1 Ligand
DISORDERED
in crystal structure = LACKS a Fixed 3D structure
Occupies Different Positions
is FLEXIBLE / DYNAMIC
OPEN / CLOSE to
ALLOW COFACTOR EXCHANGE
HDL
high density lipoprotein
TRANSPORTS CHOLESTEROL
to the LIVER for REMOVAL
How is SPECIFICITY & TIGHT BINDING
of Statins –> HMGR
Achieved?
Since the
Binding Interactions & Orientation is THE SAME
in Statins vs HMG-CoA Substrate
HYDROPHOBIC GROUPS
of the statin inhibitors = VDW interactions
are what is responsible for
tight binding = lower Ki values
FLAP DOMAIN
of HMGR
in the presence of BOTH Substrate + Cofactor
ORDERED
over the active site
when both substrate & cofactor are bound
OPEN/CLOSE
to allow cofactor exchange
Vitamin K Epoxide Reductase
Type of Enzyme // Drug // Treatment
OXIDOREDUCTASE
WARFARIN
blood clots
What type of ENZYME?
Catalyze the transfer of
Hydrogen // Oxygen // Electrons
from one molecule to another
E-Donor=reductant —> E-Acceptor=oxidant
OXIDOREDUCTASE
Ex.
HMG-CoA Reductase
Aldehyde Dehydrogenase // COX // Vit K Epoxide Reductase
Dhihydrofolate Reductase
