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
Essential Functions of Cholesterol
Source = from Diet & Synthesis from the liver
Strucural component for cell membranes
maintains fluidity & stability
synthesis of steroid hormones & bile acids
HMGR Crystal Structure
4 Monomers
with the
Active Site between them
FLAP DOMAIN
difficult to crystallize when there is 0-1 ligands bound
because it is disordered –> flexible/dynamic
How is HMG-CoA Reductase involved in
Cholesterol Biosynthesis
RATE-LIMITING STEP
Regulation of HMGR is the primary means for controlling cholesterol levels
produces Mevalonate –> Cholesterol
FEEDBACK MECHANISM
Statin’s affect on CV Disease
Statins –> REDUCE serum LDL
along with dietary changes
will decrease overall mortality
Elevated LDL –> primary RISK factor for CV disease
Lovastatin
Brand Name // Type of Inhibitor
MEVACOR
REVERSIBLE** & **COMPETITIVE
inhibitor of HMGR
Substrate - MIMIC
DiHydroFolate Reductase
DHF
Type of Enzyme // Drug // Treatment
OXIDOREDUCTASE
METHOTHREXATE & TRIMETHOPRIM
Cancer /// Bacterial Infections
HMGR
REACTION MECHANISM
Remarkable in both enzymology & biomedical relevance
- *4 Electron Oxidoreductase**
- *2-Electron Reduction** + 2-Hydride Reduction steps
2 Molecules of Cofactor = NADPH
hydride –> aldehyde –> alcohol
Cofactor Exchange Step
proceeds through 2 intermediates
FLAP DOMAIN = disordered w/ 1 or no ligands
Protein Disorder
Purpose / Function
IDRs / IDPs
is in a CONTINUIM (have everythign inbetween)
to Order TRANSITION upon BINDING
( HMGR )
TRANSIENT BINDING
FAST off/on switch
