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411 Cards in this Set
- Front
- Back
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a sensor-producer cell senses:
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stimuli/changes in environment, produces hormones
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enodcrine, paracrine, and autocrine are ALL
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hormone mechanisms
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two types of solubility of hormones:
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1. lipophilic
2. hydrophilic |
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***lipophilic cells ALWAYS: ***
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change gene expression
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lipophilic hormone *receptors* are:
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***TF's***
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hydrophilic hormones binds to cell surface receptors, =>
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relay => change in enzyme activity, cytoskeleton, transcription
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what's ALWAYS the final target of the cell relay after a hydrophilic hormone binds?
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**kinase**
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what's the most prevalent class of surface receptors?
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***GPCR***
hormone binds, activates G, G activates effector enzyme |
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what's another class of surface receptor, apart from GPCR's?
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tyrosine kinases
- ECM domain binds the hormone, cytoplasmic domain has enzyme activity (usually kinase) |
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all G-proteins cycle between
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active (GTP-bound) and inactive (GDP-bound) states
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***ALL G-proteins have inherent:***
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GTPase activity**
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rate at which a G-protein hydrolyzes GTP =
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kcat-GTP
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***Kd-GDP =
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how often GDP dissociates from G-protein
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total G-protein =
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active + inactive
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***LOWER Km =
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tighter binding = MORE activity***
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2 Positive regulators of G-proteins:
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1. GIP's
2. GEF's |
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GIP =
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GTPase-Inhibiting Protein
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what do GIP's do?
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inhibit hydrolysis of GTP by G-proteins
=> INCREASE GTP-bound state |
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GEF =
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Guanine Exchange Factor
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what do GEF's do?
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***increase*** Kd-GDP
=> increase dissociation of GDP from G-protein => increase chance of transient, empty G-protein binding GTP |
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2 Negative regulators of G-proteins:
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1. GAP's
2. GDI's |
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GAP =
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GTPase-Activating Protein
|
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what do GAP's do?
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**increase hydrolysis of GTP on G-proteins**
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GDI =
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GDP Dissociation Inhibitors
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what do GDI's do?
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inhibit dissociation of GDP from G-proteins => inactive state
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kinases take P off of ____ and attach it to _________ of a protein
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ATP;
Ser/Tyr/Thr |
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3 aspects of kinase structure:
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1. ATP-binding domain(lobe)
2. linker 3. substrate-binding domain |
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where does catalysis occur in kinases?
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at the **catalytic cleft**
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orientation of the two lobes is critical for kinase activity -
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- P anchor keeps ATP on
- activation loop on substrate-lobe is P'd to activate the kinase |
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kinases are regulated both positively and negatively;
**2nd messenger reverse: |
**negative regulation**
=> activation |
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Phosphorylation either
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activates OR inactivates
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difference between regulatory subunit and regulatory domain:
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regulatory subunit is its own protein
- domain = part of the protein |
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practice syllabus
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questions
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2 common forms of regulating kinases:
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1. 2nd messengers that activate kinases
2. other kinases |
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***negative regulations are reversed by:***
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2nd messengers
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P'ting the activation loop =>
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active kinases
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P'ting the P anchor =>
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inactivation of kinases
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reversible P'n =
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on/off switch
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where are metabolic pathways controlled?
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**at the first committed step**
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ATP and NADH INHIBIT ___________ pathways
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catabolic
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***glycolysis occurs in:***
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the cytosol of ALL cells**
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***EVERY cell uses glycolysis in:***
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the fed state
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glycolysi takes 6C and makes
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two 3C mlcls (pyruvates)
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3C pyruvates get converted to ACoA via
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pyruvate DH
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Krebs "requires" O2 in the sense that
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NADH and FADH2 are end products of Krebs, so if you don't have O2, you won't get rid of them, and they'll inhibit the cycle
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Krebs occurs ONLY in
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mit.
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products of one turn of the Krebs cycle:
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3 NADH,
2 CO2 1 GTP 1 FADH2 |
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Krebs is also called:
|
**the central pathway**
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|
in Krebs, carbs, fats, and proteins are
|
interconverted.
- ultimately where we break down what we eat |
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Oxidative P'n occurs in
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mit.
- requires O2 - produces LOTS of ATP from NADH and FADH2 |
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protein and fat metabolism *require*:
(2) |
mit. and O2
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the Pentose Phosphate Shunt occurs between:
|
glucose and pyruvate
|
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PPS exists in
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ALL cells
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PPS produces:
(2) |
1. NADH
2. ribose 5' P |
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***glycogen stored in muscles is used by
|
**those muscles only**
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muscle glycogenolysis does NOT increase
|
blood glucose
- used by those muscles |
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glycogenolysis of liver and kidney increase
|
blood glucose
|
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RBC's have NO mit.; use only
|
glycolysis and PPS
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|
|
b/c RBC's have no mit., they can't metabolize:
|
protein and fat
|
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**RBC's can't store:**
|
glycogen
- need constant supply of glucose |
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|
most of the pyruvate produced in RBC's is:
|
converted to lactate;
both are transported out of the cell in exchange for OH- |
|
|
brain cells these metabolic pathways:
(3) |
1. glycolysis
2. PPS 3. Krebs/OxP |
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brain has NO ____________
|
glycogen stores
|
|
|
the brain CANNOT use ______ as an energy source, because __________________________________
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fat;
fat cannot cross the BBB |
|
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why can't the brain use fat as an energy source?
|
fat can't cross the BBB
|
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**unlike** RBC's, brain can adapt to
|
ketone bodies if starving
|
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adipose =
|
storage of fat
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|
excess pyruvate is converted to
|
ACoA, then TG's and stored
|
|
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which energy pathways does adipose tissue use?
(2) |
glycolysis and PPS
|
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|
PPS **needs** __________ for fat synthesis
|
NADPH
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|
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adipose is NOT dependent on
|
glucose
|
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|
resting muscle uses:
(2) |
1. blood glucose
2. Krebs/OxP (once the glucose gets low), probably via FA's |
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|
muscle provides protein during
|
fasting/starvation
|
|
|
what energy sources do the liver and kidney use?
(3) |
1. glycolysis
2. PPS 3. Krebs/fat |
|
|
liver/kidney provide glucose to blood during:
(2) |
fasting, exercise
(via glycogenolysis, GNG) |
|
|
the liver/kidney does NOT depend on
|
glucose
|
|
|
the liver synthesizes TG's from
|
excess pyruvate,
exports it to adipose tissue |
|
|
"receptor" is a broad
|
term
|
|
|
**occupancy model:**
|
**effects are proportional to the DR concentration**
|
|
|
Kd =
|
affinity of drug for receptor = [ ] of drug where half of the receptors are occupied
|
|
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higher affinity =
|
lower Kd = increase in activity of receptors
|
|
|
compare the Kd between different receptors:
|
***Kd of a receptor is the same*** irrespective of which tissue it's found in
|
|
|
drugs are not specific, they're
|
selective
|
|
|
2 ways to avoid having your drug bind to all the other receptors:
|
1. increase the affinity of drug for receptor A
2. dec. the affinity for receptors B, C, D |
|
|
Occ. Model hold for occupancy vs. [D], but NOT for
|
**effects** vs. [D]
|
|
|
***response of cell is not necessarily proportional to:**
|
*occupancy*
|
|
|
EC50 =
|
[D] that produces 50% of max effect of that drug
|
|
|
potency =
|
ED50
|
|
|
efficacy vs potency
|
check
|
|
|
intrinsic vs. clinical efficacy
|
check
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a drug is more potent if:
|
it's EC50 is smaller,
**no matter what the max effect is** |
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EC50 ~
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that specific drug, no other
|
|
|
partial agonists open receptors up
|
a little, not all the way
|
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capacity of drug to bind =
|
affinity
~ strength of interaction between drug and receptor |
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capacity of drug to excite the receptor =
|
intrinsic efficacy
~ property that gives mlcls the ability to *activate* the receptor, rather than just bind to it |
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drug absorption is a function of
|
how fast it gets to the **veins**
|
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|
fastest methods of absorption, in order:
(3) |
1. IV
2.mouth/GI/skin/lungs/rectum 3. IM, SC |
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IM =
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intramuscular
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SC =
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subcutaneous
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IM and SC drugs can't handle
|
the stomach/intestine
|
|
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First Pass Effect =
|
goes to liver first
- can be good or bad for absorption |
|
|
i.e. rate of absorption depends on
|
site of administration:
IV > oral > IM > SC |
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|
bioavailability, F =
|
fraction of the dose appearing in the blood after absorption from its site of administration
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|
|
F= 1.0 ~
|
IV
- perfect availability |
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F < or = to 1.0 corresponds to
|
other sites
|
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|
what does F indicate?
(3) |
1. extent to which drug is released from its vehicle
2. failure of absorption due to degradation 3. losses due to the first-pass effect |
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|
determine F-oral via the AUC:
|
F-oral = AUC-oral / AUC-IV
|
|
|
3 facets of drug distribution:
|
1. transport
2. partition coefficient 3. competing equilibria |
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|
5 aspects of facilitated diffusion:
|
1. requires carrier protein
2. driving force = gradient 3. limited # of carriers = saturable 4. equlibrium = same amount on both side 5. NO energy expended |
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|
3 aspects of active transport:
|
1. driven by ATP
2. saturable (only a certain amount of pumps) 3. equlibrium = not the same on both sides |
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|
K-org/aq is independent of _______________________, but dependent on ________________________
|
amount and volume used;
temperature and solvent |
|
|
for calculations, treat each compartment separately; first set up
|
equilibrium in one compartment, then establish the other
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|
|
total drug may be unequal on either side of the membrane when drugs:
(3) |
1. interact with fat
2. bind to diff. proteins, to diff. extents 3. ionize to diff. extents b/c of the pH gradient b/w the two sides of a membrane |
|
|
ion-trapping =
|
how drugs will ionize and thus be taken out of the equilibrium calculation
|
|
|
WA's and WB's ionize to diff. extents on both sides of the membrane =>
|
there'll be more total drug (ionized and unionized) on the side of the membrane where ionization occurs to a greater extent
|
|
|
"ionized" =
|
has a charge
|
|
|
pKa =
|
pH at which half the protein is ionized, half is not
|
|
|
***in the fed state, EVERY cell uses:***
|
glucose
|
|
|
***brain and RBC use glucose***
|
in EVERY state
|
|
|
catabolic rxns produce:
|
ATP, NADH, FADH2
- eventually inhibit the pathways that produce them |
|
|
"irreversible" =
|
committed
|
|
|
the end product of a pathway often stimulates
|
another pathway
|
|
|
phosphorylase does 2 things:
(not phosphatase) |
1. adds P
2. cleaves its target |
|
|
transaminase transfers
|
NH3 between alpha-keto acids and AA's
|
|
|
4 facts about the Fed State:
|
1. dietary carbs are converted to glucose => blood => all cells
2. ALL cells use glucose as energy source in fed state 3. excess glucose is stored as glycogen in liver and muscle 4. excess glucose is converted to TG's in adipose and liver |
|
|
liver takes excess glucose and converts it to fat => lipoproteins =>
|
ultimately stored in adipose
|
|
|
3 facts about the Fasting State:
|
1. liver glycogen => blood glucose => brain and RBC's
2. resting muscle uses FA's 3. contracting muscles use blood glucose (from GNG), muscle glycogen, AA's, and FA's |
|
|
protein stores during fasting state:
(2) |
1. broken down into AA's => GNG => blood glucose => brain and RBC's
2. contracting muscle uses its own AA's |
|
|
fat stores during fasting state:
(2) |
1. **adipose => FA's => primary energy source for most tissues EXCEPT for brain and RBC's**
2. contracting muscles use FA's |
|
|
the brain adapts to ketone bodies when there are no longer any
|
unessential protein stores
|
|
|
as dietary glucose gets taken up, liver glycogen
|
starts getting broken down
- and in the middle of that, GNG starts |
|
|
anaerobic exercise =
|
high intensity, short duration
|
|
|
anearobic exercise ~ mostly fast-twitch muscles => few mit. =>
|
**fat is poorly utilized**
|
|
|
***b/c circulation is limited during an. exercise, blood glucose:***
|
is NOT utilized well
- so fat and blood glucose are not serious sources of energy for anaerobic muscle during exercise - buildup of lactic acid is limiting |
|
|
primary sources of energy in muscle during anaerobic exercise:
(3) |
1. ATP
2. CP 3. muscle glycogen - muscle primarily uses "onboard" sources |
|
|
sources of energy for muscles during aerobic exercise:
|
1. blood glucose
2. then liver glycogen 3. then fat |
|
|
***fat can provide more than ___% of the calories for endurance exercise
|
70%
|
|
|
limitations of aerobic exercise:
(3) |
1. glycogen stores running out
2. O2 / fat transport to the mit. 3. rate of OxP |
|
|
Glucagon and EPI receptors =
|
B-adrenergic
|
|
|
Glucagon role:
(2) |
1. increase blood sugar
2. increase release of alternate sources of energy - i.e. fat |
|
|
Glucagon effects:
(3) |
1. increase glycogenolysis in liver
2. inc. GNG 3. **inc. lipolysis in adipose** |
|
|
Glucagon has NO effect on
|
muscle
- b/c muscle glycogen is never exported - muscle don't even have Glucagon receptors |
|
|
protein breakdown occurs in muscle when there's a lack of
|
insulin
|
|
|
role of EPI:
|
increase mobilization of energy sources
|
|
|
effects of EPI:
(6) |
1. inc. glycogenolysis in liver
2. inc. GNG 3. inc. lipolysis in adipose 4. inc. proteolysis in **skeletal muscle** - all *provide* energy for muscle 5. inc. glycogenolysis in muscle 6. inc glycolysis in muscle - *use* energy in muscle |
|
|
role of insulin:
(2) |
1. dec. blood glucose (inc. uptakte)
2. inc. use of glucose in cells |
|
|
effects of insulin:
(6) |
1. inc. uptake by muscle and adipose
2. inc. of glycolysis in liver and adipose 3. inc. glycogenesis 4. inc. conversion of glucose to fat 5. inc. export of fat from liver to adipose 6. **inc. protein synthesis** |
|
|
the liver is insulin-__________
|
INDEPENDENT
|
|
|
cori =
|
lactic acid cycle
|
|
|
***all 3 hormones - GLUC, EPI, IN - are present in the blood at all times; relative ratios =>
|
net effect
|
|
|
diabetes =
|
low IN/GLUC
or low IN / EPI |
|
|
dietary sugars => breakdown => bloodstream => liver =>
|
conversion to glucose => blood => cells
|
|
|
cataracts occur b/c of which enzyme?
|
aldose reductase
- it's nonspecific, and will convert any sugar with an aldehyde group - of which glucose is one - no transport for sorbitol => accumulation in eye => osmotic changes => cataracts |
|
|
low Km = effective at low concentrations of ligand =
|
higher effectiveness / affinity
|
|
|
glucose has _____ different tranporters
|
many
|
|
|
basal transport of glucose is a feature of:
|
brain and RBC's
|
|
|
**transporters active only in the fed state are clearly insulin-dependent; what are 2 examples of such tissues?
|
**adipose and muscle**
|
|
|
GLUT 2 cells SENSE when blood glucose is high - found on
|
liver, pancreas
have a **high Km** - only take glucose up when it's HIGH in the blood |
|
|
GLUT 4's are normally insulin-dependent but ______________________ can also activate them
|
**muscle contraction**
- GLUT 4 can be active without insulin around |
|
|
insulin =
|
master hormone
|
|
|
insulin drives the
|
recovery process
|
|
|
***when is muscle sensitized to insulin?***
|
during exercise AND 6-8 hours afterward
|
|
|
(dietary AA's also stimulate insulin release from
|
B-islet cells)
|
|
|
**post-workout meal should be:**
|
carbs AND protein
- carbs => insulin release, which uptakes glucose AND inc. muscle synthesis - protein => muscle synthesis |
|
|
an exercising Type I diabetic should reduce their insulin both during and after exercise - why?
|
b/c exercise *sensitizes* muscles to insulin both during and after the workout
=> need less insulin |
|
|
hexokinase/glucokinase P'n accomplishes 2 things:
|
1. prepares glucose for glycolysis
2. keeps glucose in the cell |
|
|
3 facets of hexokinase:
|
1. found in most tissues
2. low Km 3. inhibited by G6P |
|
|
where is glucokinase found?
2 facets: |
**in the liver and B-islet cells;**
1. high Km 2. NOT inhibited by G6P |
|
|
glycolysis: net input and net output:
|
2 ATP in;
2 net ATP, 2 NADH out (0 NADH if anaerobic exercise) |
|
|
4 key enzymes of glycolysis:
|
1. hexo/glucokinase
2. PFK 3. pyruvate kinase 4. lactate DH |
|
|
what's the primary control point for glycolysis?
|
***PFK***
|
|
|
PFK is activated by:
|
1. ***F2,6 bisP***
(2nd messenger) 2. AMP, etc. |
|
|
PFK is inhibited by:
(4) |
1. ATP
2. **low pH (glycolysis produces protons)** 3. NADH 4. citrate |
|
|
what's the secondary control point of glycolysis?
|
**pyruvate kinase**
|
|
|
pyruvate kinase is activated by:
(2) |
1. G6P
2. F1,6 bisP |
|
|
pyruvate kinase is inhibited by:
(3) |
1. ATP
2. NADH 3. ACoA |
|
|
4 key enzymes of glycolysis all correspond to
|
irreversible rxns
|
|
|
PFK =
|
allosteric enzyme
|
|
|
F2,6 bisP amplifies glycolysis b/c it:
(2) |
1. inc affinity of PFK for F6P
2. dec. inhibition of PFK by ATP |
|
|
***amplified glycolysis occurs under these conditions:***
(4) |
1. ***no mit.*** (i.e. in RBC's)
2. intense exercise (limited O2) 3. in many tumor cells 4. when F2,6 bisP is increased |
|
|
amplified glycolysis occurs in exercising muscles because:
|
inhibitors are low, and F2,6 is high
- but even amplified glycolysis is limited by lactic acid |
|
|
2 problems with NADH:
|
1. NADH inhibits glycolysis
2. NADH can't normally get **INTO** the mit. through the membrane |
|
|
amplified glycolysis occurs in exercising muscles because:
|
inhibitors are low, and F2,6 is high
- but even amplified glycolysis is limited by lactic acid |
|
|
prob. 1: NADh inhibits glycolysis; Solution =
|
**lactate DH** regenerates NAD+ for glycolysis
- rxn is *reversible* - *driven by mass action* |
|
|
2 problems with NADH:
|
1. NADH inhibits glycolysis
2. NADH doesn't cross the mit. membrane |
|
|
liver ***also has lactate DH*** => inc. lactate =>
|
dec. pyruvate => rxn driven left => inc. pyruvate => GNG
(Cori cycle) (mass action) |
|
|
prob. 1: NADh inhibits glycolysis; Solution =
|
lactate DH regenerates NAD+ for glycolysis
- rxn is reversible - driven by mass action |
|
|
Prob 2: NADH can't get INTO the mit. through the mit. membrane;
Solution = |
shuttle system
|
|
|
liver also has lactate DH => inc. lactate =>
|
dec. pyruvate => rxn driven left => inc. pyruvate => GNG
(Cori cycle) |
|
|
2 shuttle systems for NADH:
|
1. glycerol P shuttle
2. malate shuttle |
|
|
Prob 2: NADH can't get into the mit. through the mit. membrane;
Solution = |
shuttle system
|
|
|
glycerol P shuttle:
(3) |
1. used by most cells
2. generates 2 ATP per NADH 3. ***regenerates cystolic NAD+ for glycolysis*** |
|
|
2 shuttle systems for NADH:
|
1. glycerol P shuttle
2. malate shuttle |
|
|
malate shuttle:
(3) |
1. used in heart muscle
2. generates 3 ATP per NADH 3. used for biosynthetic pathways |
|
|
glycerol P shuttle:
(3) |
1. used by most cells
2. generates 2 ATP per NADH 3. regenerates cystolic NAD+ for glycolysis |
|
|
biosynthetic =
|
anabolic
|
|
|
malate shuttle:
(3) |
1. used in heart muscle
2. generates 3 ATP per NADH 3. used for biosynthetic pathways |
|
|
purpose of GNG:
|
blood glucose must be constant
- GNG supplies constant glucose to blood during fasting and exercise |
|
|
biosynthetic =
|
anabolic
|
|
|
purpose of GNG:
|
blood glucose must be constant
- GNG supplies constant glucose to blood during fasting and exercise |
|
|
most of the substrates used for GNG are
|
AA's
|
|
|
4 sources of pyruvate for GNG:
|
1. lactate from amplified glycolysis in RBC's and exercising muscle
2. AA's from exercising muscle 3. AA's mobilized during fasting 4. glycerol mobilized during fasting |
|
|
metabolic pathways =
|
mostly reversible rxns driven by a few irreversible rxns
|
|
|
**very unusual fact:**
|
glycolysis (catabolic) and GNG (anabolic) use many of the same enzymes
|
|
|
GNG reverses ___________________________________
|
the 7 reversible steps of glycolysis
- and BYPASSES the irreversible ones, using a different set of enzymes |
|
|
what do most anabolic pathways use as a substrate?
what does GNG use? |
most use NADPH;
GNG uses **NADH** (since it uses many of the same enzymes as glycolysis) |
|
|
GNG requires:
(2) |
1. 6 ATP
2. 2 NADH |
|
|
muscle has all the enzymes for GNG except:
|
***glucose-6-phosphatase***
- no functional GNG (can't release glucose into blood) |
|
|
pyruvate carboxylase adds:
|
CO2 to pyruvate => OAA
|
|
|
**ALL carboxylases require:**
|
**biotin** as a cofactor
|
|
|
pyruvate carboxylase rxn occurs in the
|
mit.
|
|
|
OAA that pyruvate carboxylase creates can't
|
**leave the mit.**
- so converted to Asp. |
|
|
PEP carboxykinase does 2 things:
|
1. P's (takes P from GTP)
2. decarboxylates (cleaves CO2) |
|
|
**carboxylation/decarboxylation drive:
|
very unfavorable rxns
|
|
|
neither pyruvate carboxylase nor PEP carboxykinase are unique to GNG, so they can't be control points; what IS the primary control point of GNG?
|
***F1,6 bisPhosphatase enzyme***
- **exact opposite of PFK** |
|
|
GNG is inhibited by:
(2) |
1. F2,6 bisP
2. ADP |
|
|
GNG is activated by:
(2) |
1. ATP
2. NADH |
|
|
glucose-6-phosphatase is found only in
|
the liver and kidney = > able to get glucose for blood
- opposite of hexo/gluco |
|
|
compare the primary control points of glycolysis vs GNG
|
glycolysis ~ PFK, activated by F2,6 bis P
GNG ~ FBP, inhibited by F2,6bisP |
|
|
F2,6 bisP regulates PFK and FBP, and in turn is regulated by:
|
***PFK-2/FBP-2 enzyme***
|
|
|
PFK-2/FBP-2 =
|
one enzyme with 2 catalytic sites and 1 regulatory site
|
|
|
****dePhosphorylation of PFK-2/FBP-2 =>
|
PFK-2 site activated => F6P converted to F2,6 bisP => inc. glycolysis
(and dec. GNG) |
|
|
****Phosphorylation of PFK-2/FBP-2 =>
|
activation of FBP-2 site => F2,6 bisP hydrolyzed to F6P
=> increased GNG (and dec. glycolysis) |
|
|
****Insulin =>
|
dePhosphorylation of PFK-2/FBP-2
- follow through with what happens |
|
|
****Glucagon/EPI =>
|
Phosphorylation of PFK-2/FBP-2 => activation of FBP-2 site
- follow through with the rest - draw it out like nobody's business |
|
|
for most pathways, Glucagon and EPI *directly* P rate-limiting enzymes; but in glycolysis/GNG, they
|
P a *regulatory enzyme* that's NOT in the pathway, which then controls levels of a 2nd messenger
|
|
|
***when is Glucagon is released?***
|
**when blood glucose decreases**
|
|
|
****EPI effect in muscle is
|
OPPOSITE to that in the liver
=> INCrease in glycolysis, DECREASE in GNG in the muscle |
|
|
why is EPI effect on muscle the opposite of that on the liver?
|
**b/c muscle has a PFK-2/FBP-2 isozyme that does the opposite of the regular one**
|
|
|
signal amplification: ultimately, characteristics of the tissue determine the response; 3 characteristics:
|
1. density of receptors
2. amounts of downstream signaling proteins 3. degree of amplification b/w signaling mlcls |
|
|
**often, we don't have to activate ALL the surface receptors to see
|
MAX effect
- usually, b/c all G-proteins are activated by the few bound receptors e.g. EPI => cAMP => kinase |
|
|
even though affinity for the drug is equal for all tissues, the potency of an agonist
|
can vary between those same tissues
|
|
|
intrinsic efficacy =
|
capacity of a drug to activate a receptor
|
|
|
clinical efficacy =
|
whether a drug produces a desired clinical effect
|
|
|
potency = EC50 =
|
concentration of a drug necessary to produce 50% of the MAX effect of THAT drug
- different for each drug |
|
|
***lower EC50 =
|
more potent drug
|
|
|
one way to stop diseases is to put brakes in the signalling pathway, i.e.
|
add antagonists
|
|
|
2 kinds of antagonists
|
1. competitive antagonists
2. noncomp antagonists |
|
|
competitive antagonists are surmountable by increasing the agonist,
|
noncomp are not
|
|
|
3 mechanisms of noncomp antagonism:
|
1. antagonist binds to the receptor irreversibly, thereby taking it out of commission (considered noncomp b/c it's insurmountable)
2. antagonist binds at allosteric pocket 3. antagonist inhibits a downstream step |
|
|
***just like enzyme curves, noncomp will
|
have a lower max effect, but will keep EC50 the same
|
|
|
allosteric enzymes influence
|
the ability of the natural ligand to effect change
|
|
|
zwitterion =
|
AA with BOTH a positive and negative charge
|
|
|
alpha-AA =
|
regular AA
|
|
|
AA's are *easily* converted to
|
alpha-KETO acids
- NH3 removed, = O added instead |
|
|
which enzyme is responsible for the interconversion b/w aAA's and aKeto's?
|
**transaminases**
|
|
|
***a steady equilibrium exists between AA's and proteins***
|
continuous synthesis = continuous degradation
|
|
|
3 facets of lysosomal degradation:
which AA chain signals elimination? |
1. general/non-selective
2. degrades proteins from both cytosol and ECM 3. ***K-F-E-R-G signals degradation*** (sparing essential proteins) |
|
|
lysosomes are
|
proteases
|
|
|
Ub-Proteosome is more specific; 3 facets of Ub degradation:
|
1. Ub is recycled
2. more Ub's = more-rapid degradation 3. hydrophobic AA's on Ub = slow degradation |
|
|
true Nitrogen balance:
|
N in = N out
|
|
|
AA catabolism is ALWAYS going on,
|
no matter what
|
|
|
2 ways to remove amino groups:
|
1. transamination
2. deamination |
|
|
NH3 =
|
ammonia
|
|
|
what happens to NH3 once it's removed form a mlcl?
|
it's brought to the liver, converted to urea, and excreted in urine
|
|
|
another name for aKeto acids =
|
C-skeletons
|
|
|
what happens to C-skeletons?
|
**they get oxidized to CO2 via Krebs**
=> ATP OR converted to glucose (for brian/RBC's) or fat (stored as TG's) |
|
|
NH3 is
|
toxic
|
|
|
urea:
(2) |
1. water-soluble
2. non-toxic |
|
|
glutamate =
|
alph-keto acid carrying NH3
|
|
|
glutamine =
|
alpha-keto acid carrying TWO amino group's
|
|
|
*glutamate has a central role in
|
AA and N metabolism
|
|
|
***pyroxitol P = ***
|
coenzyme for ***transaminase***
|
|
|
**Vit B6 = precursor of
|
pyroxitol P
|
|
|
what does glutamate DH do to NH3?
|
clips it off, or adds it
|
|
|
glutaminase removes
|
NH3 form glutamine
|
|
|
glutamine synthase adds
|
NH3 to glutamate, making glutamine
|
|
|
"keto" =
|
missing NH3
|
|
|
**the NH3 acceptor is almost always**
|
aKG
|
|
|
where is free NH3 found?
|
**in ALL tissues**
|
|
|
**most tissues ship ammonia to liver and kidney as
|
glutamine
|
|
|
kidney takes NH3 and converts it to
|
NH4+ => urine
|
|
|
surplus AA's are NOT
|
stored
- they are either used or catabolized |
|
|
NH3's are collected on glutamate, while C-skeletons =>
|
ATP, fat, and GNG
|
|
|
****what's the control point of the urea cycle?****
|
Carbamoyl-P synthase
- "activates" NH3 |
|
|
arginase:
(2) |
1. ***in liver only***
2. makes urea, regenerates ornithine |
|
|
arginine =
|
ornithine w/ urea sticking out
|
|
|
urea cycle failure =>
|
death
|
|
|
**carbamoyl Phosphate =
|
"activated" NH3
|
|
|
how much ATP does it cost to make urea?
|
4 ATP
|
|
|
the AA's carrying NH3 to liver are:
|
1. Gln (x2)
2. Glu 3. Ala |
|
|
***what's the one thing that ACoA CANNOT do is be made into?***
|
glucose
- ACoA does not enter GNG |
|
|
gluconeogenic C-skels =>
(2) |
1. feed into Krebs
2. become pyruvate => OAA => GNG |
|
|
glucogenic C-skel pyruvate pathway:
|
pyruvate => OAA => Ala => liver => glucose via GNG
|
|
|
ketogenic C-skels => **ACoA** =>
|
1. oxidized for energy
2. stored as TG's 3. converted to ketone bodies |
|
|
muscle proteins broken down =>
|
20 AA's
glucogenic => GNG ketogenic => ATP |
|
|
protein quality of egg, soy, and milk =
|
1.0
- have ALL 20 AA's |
|
|
NH3 becomes urea in both
|
fed and fasting state
|
|
|
1C metabolism is a result of
|
AA degradation
|
|
|
transfer of 1C units in various oxidation states is required for
|
synthesis of many important mlcls
e.g. NT's |
|
|
***1C units can be carried by only 2 cofactors:***
|
1. THF
2. SAM |
|
|
THF is made from
|
***folic acid***
|
|
|
folic acid is
|
**essential**
- must obtain from diet |
|
|
****what's the enzyme that's absolutely necessary to both generate and regenerate THF and DHF?****
|
DHF Reductase**
|
|
|
you MUST have THF for
|
DNA, cell division
(precursor of Purines, Thymidine) |
|
|
purines =
|
AG, bigger
(CT is smaller) |
|
|
DHFR synthesis inhibitors are
|
chemotherapy drugs => prevent synthesis of Purines, NT's
|
|
|
name a DHFR inhibitor:
|
Methotrexate
|
|
|
SAM =
|
MAJOR methyl donor
- transfers CH3 to NOR, EPI |
|
|
regeneration of methionine from homocysteine requires:
(2) |
1. folic acid
and 2. B12 cofactors |
|
|
conversion of homocysteine to cysteine requires
|
Vit. B6
|
|
|
increase in blood homocysteine =
|
inc. risk of CVD
|
|
|
***dietary supplements of folic acid, B12, and B6 =>
|
decrease in blood homocystiene => dec. risk of CVD
|
|
|
***folate deficiency causes
|
neural tube defects BEFORE you know you're pregnant
|
|
|
**elevated homocysteine is usually due to
|
mutations in cysteine synthase
|
|
|
once drugs enter the plasma, they
|
spread, bind and go to different tissues
|
|
|
Q =
(meaning, not equation) |
mols of drug in the body
|
|
|
Vd =
|
*apparent* volume into which drug has dissolved
- a m. of the extent to which drug has distributed in the body - m. in Liters |
|
|
C =
|
plasma concentration of drug,
in mol/L of plasma |
|
|
***higher Vd =
|
LESS drug free in the plasma
= decreased C |
|
|
Vd is different for
|
each drug
|
|
|
**using IV =
|
NO elimination**
|
|
|
Q =
|
Vd x C
|
|
|
3 ways to express Vd:
|
1. in L
2. in L/kg 3. as % body weight (L/kg x 100%) |
|
|
factoring in Bioavailability, F:
|
1. do regular IV calculaiton first: find Q
2. then divide Q by F |
|
|
ICW =
|
water in tissue cells, blood *cells*
|
|
|
ECW =
|
water in intersitium, plasma
|
|
|
C always means
|
C Unbound, drug that's free in plasma
|
|
|
***you can only say that ALL of a drug is in the plasma if
|
Vd = Plasma Concentration of Water
|
|
|
you can only say that all of the drug distributed EVERYWHERE if:
|
Vd >TBW
|
|
|
basal state DOES NOT mean
|
active state
|
|
|
agonists =
|
drugs that favor the active state of the receptor
|
|
|
competitive antagonists =
|
drugs that favor neither the active nor the inactive state
|
|
|
competitive antagonists are also called
|
neutral antagonists
|
|
|
inverse agonists =
|
drugs that favor the inactive state of receptors
|
|
|
inverse agonists are also called
|
negative antagonists
|
|
|
agonists bind to the active state of the receptor,
|
keeping in active
|
|
|
inverse agonists favor/bind to the inactive state of a receptor,
|
keep it inactive
|
|
|
inverse agonists inhibit
|
basal activity
|
|
|
basal activity =
|
activity that occurs **independent of agonists/antagonists**
- some amount of receptors is always changing conformation between the active and inactive states |
|
|
"constitutive activity" =
|
basal activity
|
|
|
inverse agonists are perfect for
|
disease that don't respond to competitive antagonists
e.g. human herpes virus |
|
|
3 facets of inverse agonists:
|
1. bind orthosteric site
2. block ability of agonists to bind 3. inhibit basal activity |
|
|
graded response =
|
effect increases as dose increases
|
|
|
Quantal response =
|
effect occurs OR doesn't occur
- a matter of frequency |
|
|
quantal dose response curves ~
|
concentration at which a dose gives an all-or-none effect
|
|
|
QRD curves do NOT
|
relate the magnitude of the effect to the dose
|
|
|
pharmacodynamic variability =
|
how the response will be different based on age, genetic, etc
|
|
|
the slope of the *cumulative* freq. curve relays the response of
|
the population
- diff. pop. => diff. slope |
|
|
bell curve =
|
freq. distribution
|
|
|
therapeutic index =
|
TD50 / ED50
|
|
|
TD50 =
|
dose at which 50% of those receiving the drug will experience toxicity
|
|
|
the ideal therapeutic window includes:
|
***max effect w/o ANY toxicity***
|
|
|
different slopes of effect and toxicity =>
|
new therapeutic window
|
|
|
Certain Safety Factor =
|
TD 1 / ED 99
|
|
|
***CSF of greater than or equal to 1 is best;***
|
<1 means you're knowingly causing toxicity
|
|
|
chemotherapy usually has CSF
|
<1
|
|
|
Vd relates:
|
plasma concentration of drug relative to amount in body
|
|
|
Cl relates:
|
the plasma concentration of the drug to its elimination from the body
|
|
|
the liver metabolizes drugs, makes them more polar, and
|
sends them to the kidneys, where they are eliminated in urine
|
|
|
***what's the primary mechanism of elimination?***
|
Bowman's capsule
|
|
|
what are the secondary mechanisms of elimination?
|
1. secretion into kidney tubules
2. reabsorption from kidney tubules |
|
|
P*CL =
|
UV
|
|
|
P =
|
C = concentration of unbound drug in plasma,
- mg/ml |
|
|
Cl =
|
amount of plasma that can be cleared of drug each minute
- ml/min |
|
|
U =
|
urine concentration of the drug
- mg/ml |
|
|
V =
|
rate of urine production
- ml/min |
|
|
**UV** =
|
mg of drug eliminated per minute
|
|
|
GFR =
|
130 mg/min
|
|
|
Inulin is NOT subject to
|
ANY secretion or reabsorption
|
|
|
Cl of inulin =
|
130 mg/min
|
|
|
**if Cl of drug is > Cl of inulin, then
|
secretion MUST have occurred
|
|
|
**if Cl of drug is < Cl of inulin, then
|
reabsorption of drug MUST have occured
|
|
|
zero-order: k is a
|
FIXED rate, with units
|
|
|
first-order: rate changes with
|
change in concentration
k = fraction, 1/sec |
|
|
ke =
|
overall rate of elimination
|
|
|
first-order: increase drug in plasma =>
|
increase elimination
|
|
|
steady-state is reached when rate of elimination =
|
plasma concentration
|
|
|
****it takes 4 to 5 hours for:****
(3) |
1. 93-97% of drug to be eliminated
2. drug to reach Css 3. drug to reach new Css when you change the dose at the original Css |
|
|
MDoral = oral maintenance dose =
|
oral dose necessary to maintain Css
|
|
|
for some drugs, elimination can be
|
saturated
|
|
|
when dose exceeds amount that can be eliminated, regular dosing no longer
|
produces a steady state
- i.e. drug exhibits zero-order, fixed rate |
|
|
***inc. K org/aq =
|
increase lipophilicity
(affinity for fat) |
|
|
|
|
|
|
First Pass Effect can be
|
good OR bad for drug's effect
|
|
|
ion-trapping ~
|
given portion of your drug that will ionize and be taken OUT of eq
|
|
|
pre-pro-hormone signal =
|
hydrophobic AA seq. that sends it to the ER
|
|
|
flanking sequences of pro-hormones =
|
dibasic AA's
- KK, KR, RK, RR |
|
|
flanking sequences are cleaved in
|
Golgi, secretory vesicles
|
|
|
***conversion of pro-hormones to mature hormones is catalyzed by:
|
Pro-hormone Converting enzymes
- PC's |
|
|
PC's cleave
|
the dibasic AA sequences
|
|
|
The Signal Recognition peptide on the ER membrane has a protease that:
|
cleaves the signal off the pre-pro-hormone, so that the pro-hormone can enter the ER
|
|
|
polypeptide hormones are ALWAYS synthesized as
|
pre-pro-hormones
- then processed in secretory pathway to yield mature hormones |
|
|
**2 reasons for processing polypeptide hormones:**
|
1. insure secretion into ER
2. delay activation of hormones |
|
|
***3 gene-precursor relationships:***
|
1. one gene can encode the precursor of a single hormone
e.g. insulin 2. one gene can encode a precursor with MULTIPLE copies of a single hormone e.g. gene for pre-pro-enkephalin 3. one gene can encode the precursor of a number of DIFFERENT hormones (with diverse biological functions) (e.g. POMC) |
|
|
pre-POMC is synthesized by 3 diff tissues; synthesis at each is controlled by
|
which hormones these tissues respond to
|
|
|
furthermore, POMC is processed differently in diff. cell types to produce
|
diff mature hormones
- ***determined by which PC's are expressed in these cells*** |
|
|
POMC deficiency =
|
a big deal
- no adrenal hormones - obesity - red hair |
|
|
plieomorphic =
|
more than one
|
|
|
pleiomorphic *phenotypes* occur as a result of:
|
mutation(s) in a single gene that encodes more than one hormone
e.g. pre-POMC gene |
|
|
mutations with PC's also cause many problems; for example, if PC1 is mutated,
|
C-peptide of insulin is NOT clipped,
=> inactive pro-insulin released into circulation |
|
|
***2 disruptions that cause LOTS of problems:***
|
1. mutations of a gene that encodes for >1 mature hormone
2. mutations of PC enzymes that process multiple prohormones into mature hormones |
|
|
PC's are
|
***serine proteases***
|
|
|
rough ER ~ ribosomes ~
|
~ protein synthesis
|
|
|
uptake of pre-pro-hormone begins
|
DURING translation
|
|
|
diff. products are produced by diff cells depending on
|
1. presence of receptors for positive stimuli
2. presence of PC enzymes specific to diff. processing sites |
|
|
PPS of RBC's =>
|
membrane protection from ROS
|
|
|
GNG plays a major role in ridding the body of:
|
lactate
- via the Cori cycle |
|
|
Fed State:
(3) |
1. blood glucose supplies ALL tissues
2. excess glucose converted to glycogen in liver, kidney, and muscle 3. excess glucose converted to fat in adipose and liver (which brings it to adipose via lipoproteins) |
|
|
Fasting State:
(2) |
1. liver glycogen => glucose for brain and RBC's
2. all other tissues use FA's from lipolysis |
|
|
Prolonged Fasting:
(2) |
1. muscle protein broken down to supply AA's for GNG => brain and RBC's
2. all other tissues still use FA's |
|
|
Starvation:
(1) |
brain adapts to ketone bodies
|
|
|
in general, ***Exercising Muscle uses:***
(4) |
1. blood glucose
2. muscle glycogen 3. FA's 4. AA's from its own breakdown |
|
|
energy sources for muscles during Anerobic Exercise:
(3) |
1. CP
2. ATP 3. muscle glycogen (blood glucose can't get into the muscle fast enough) |
|
|
energy sources for muscles during Aerobic Exercise:
|
1. liver glycogen
2. ***FAT*** (>70%, as liver glycogen decreases) 3. Cori cycle (=> glucose) |
|
|
***Endurance exercise is a special case: Fat can only supply:
|
50% of energy needs
- glycogen stores are most important - that's why carb-loading was invented |
|
|
glucose can support ___ of VO2 max, while fat can supply ____________ during *endurance* exercise
|
100%;
only 50% of VO2 max |
|
|
fat can only supply 50% of
|
VO2 max
|
|
|
as soon as you see EPI, you should be thinking
|
exercise
- whether the body is in a fed state or fasting state is unimportant |
|
|
the Cori cycle recycles lactate from
|
RBC's and exercising muscle
- liver converts it to glucose |
|
|
lactate can be used as an energy source by
|
some tissues
|
