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248 Cards in this Set

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  • Back
What are the 2 fxns of endocytosis?
bring material into cell
recycle cell membrane
Do both phagocytosis and pinocytosis have cytoskeletal involvement?
only phagocytosis and MACROpinocytosis requires cytoskeleton
What does pinocytosis involve?
cell drinking
clathrin-coated pits
caveolin-coated caveolae
ingesting SMALL particles
The fusing of phagosome with lysosome gives you?
Where are the professional phagocytes derived from? What are they?
from Bone Marrow
macrophages, neutrophils, and dendritic cells
Phagocytosis involves a rearranging of what?
actin cytoskeleton rearrangement
involves cell signalling
What process is "triggered" by receptor (antibody, FcRs) and activated by complement, sugars on the surface, or plasma membrane lipids?
Describe the zippering model of phagocytosis.
The Fc R on phagocytes bind to complement binding Igs (IgG) expressing Ag. The particle (opsonized) is now tethered to the membrane and a zippering process drives the initial extension of membrane
Recruitment of actin cytoskeleton pushes plasma membrane aournd target
cell is engulfed
What is an active process triggered by the stimulation of Fcg receptors?
Describe why phagocytosis is considered a triggered process?
Antibodies bound to these bacteria, enable them to be ingested and degraded through interaction of the multiple Fc domains arrayed on the bacterial surface with Fc receptors on the phagocyte surface. Antibody coating also induces activation of the complement system and the binding of complement components to the bacterial surface (opsonization). These can interact with complement receptors (for example CR1) on the phagocyte. Fc receptors and complement receptors synergize in inducing phagocytosis
How does cell signaling lead to final engulfment?
Binding of Fc and complement receptors signals the phagocyte to increase the rate of phagocytosis, fuse lysosomes with phagosomes, and increase its bactericidal activity.
In phagocytosis, what pushes plasma membrane around target?
formation of actin network..rearrangement of actin cytoskeleton
How is Tb acquired?
from M. Tuberculosis bacteria acquired by inhalation into the lungs, where it is phagocytosed by alveolar macrophages.
How do the macrophages of most healthy individuals, with the help of the adaptive immune system, contain the infection?
within a lesion called a tubercle. In most cases, the lesion becomes walled off within a fibrous capsule that undergoes calcification, after which it can easily be seen on an X-ray of the lungs of an infected person.
How does M. tuberculosis prevent phagolysosome formation?
by interfering with Rabs (prevent maturation of phagolysosome)
What is the unusual feature of M. tubercolosis?
it can survive for decades w/n macrophages contained in tubercles but can become reactivated when the host becomes immunocompromised and spread in lung and other organs
What enzyme is involved in the synthesis of reactive oxygen species?
NADPH oxidase on phagosome
Describe the respiratory burst?
Upon phagocytosis, macrophages and neutrophils also produce a variety of other toxic products that help kill the engulfed microorganism. The most important of these are hydrogen peroxide (H2O2), the superoxide anion (O2), and nitric oxide (NO), which are directly toxic to bacteria. They are generated by lysosomal NADPH oxidases and other enzymes in a process known as the respiratory burst, as it is accompanied by a transient increase in oxygen consumption.
Can both macrophages and neutrophils survive the respiratory burst?
only macrophages
neutrophils do not
Dead and dying neutrophils are a major component of the pus that forms in some infections
What does green pus indicate?
abundance of copper myeloperoxidase
What is Legionnaire's treated with?
antibiotic erythromycin
How does one aquire Legionnaire's disease?
inhaling water droplets with L.pneumophilia and or infected amoebae--bacteria then invade/live inside alveolar macrophages
What is the classic sign of legionella infxn?
coiled phagosome
whorls of cell membrane encircling
How is the Legionnaire's pathogen spread?
by A/C b/c amoebae grow well in AC cooling towers
How does L. monocytogenes escape phagocytosis?
It is taken up into cells via the zipper mechanism and secretes a protein called hemolysin that forms large pores in the phagosomal membrane, eventually disrupting the membrane and releasing the bacteria into the cytosol. Once in the cytosol, the bacteria continue to secrete hemolysin and replicate, but it does not destroy the plasma membrane
What happens to the hemolysin secreted by L.monocytogenes?
it has a degradation signal on it, so once the pathogen has escaped into the cytosol, the hemolysin is destroyed by host proteosomes so that the host cell plasma membrane stays in tact
How is L. monocytogenes aquired? How is it phagocytosed?
common food borne pathogen--by food poisoning.
Binds to E-Cadherin on epithelial cells and is phagocytosed
Familial Hypercholesterolemia is a form of what?
What are the characteristics of FH?
high LDL cholesterol, Xanthomas (especially tendons), Xanthelasmas (plaques on eyelid), lipid deposition in cornea
What did the the study of LDL-R lead to?
understanding of receptor-mediated endocytosis and its dependence on RECEPTOR RECYCLING
Describe the classes of LDL-R defects.
In some persons with this disorder, the LDL receptor is simply not produced(Class 1);
Class 2: most common; R made but not moved from ER to membrane
Class 3: R reaches membrane but can't bind normally
Class 4: mutant receptor binds LDL normally but the LDL-receptor complex cannot be internalized by the cell and is distributed evenly over the cell surface rather than confined to clathrin-coated pits
Class 5: defects in R recycling
In Class 4 FH, why can't the LDL-R's interact with clathrin effectively?
b/c they cannot bind to adaptins, and fail to cluster in coated pits
What is the fxn of adaptins?
driving force for formation of clathrin coated pits
What are the 4 roles of AP complexes in controling coated vesicle formation?
1. selectively targeted to specific cellular membranes
2. trigger assembly of clathrin lattice role in concentrating cargo into coated pits
4.regulated by pH, inositolphosphates, phosphorylation/dephos, and GTPases
What do adaptins bind?
The adaptins bind both clathrin triskelions and membrane-bound cargo receptors
What does the cytoplasmic R tail bind to in the formation of a vesicle?
binds to adaptin directly
binds INDIRECTLY to clathrin
What is Dynamin and what is its fxn?
Cytosolic GTPase that binds to the neck of a clathrin-coated vesicle in the process of budding from the membrane, and which is involved in completing vesicle formation.
What happens once the vesicle is released from the membrane?
A chaperone protein of the hsp70 family functions as an uncoating ATPase, using the energy of ATP hydrolysis to peel off the coat
Another protein called auxillin, which is attached to the vesicle, is believed to activate the ATPase
What is occuring in Class 3 FH?
N-terminal LDL-binding domain is mutated and LDL-R can't bind LDL
What is occuring in class 4 FH?
cytoplasmic tail of LDL-R lacks the internalization signal aa and therefore does not bind to adaptin and cluster in coated pits
four-residue sequence in the cytosolic domain is crucial for internalization: Tyr-X-X-ø, IN Class 4, Tyr is exchanged for Cys!!!
What are caveolae and where are they found?
present in plasma membrane of most differentiated cells especially ENDOTHELIAL cells
Major structural protein
What is the fxn of caveolae?
participate in transcytosis as well as endocytosis
CLATHRIN-INDEPENDENT endocytosis in which involves the uptake of molecules in small invaginations of the plasma membrane called caveolae
In the plasma membrane, where are caveolae concentrated?
form from lipid rafts (rich in cholesterol, glycosphingolipids, GPI-proteins, and signaling molecules)
How can you id caveolae?
they look like flask invaginations and stain light in color
They have a spiked-coat morphology compared with clathrin coat
How do caveolae pinch off plasma memb?
using dynamin
What are the 2 important roles of caveolae?
stuctrual role
cell signalling role by acting as scaffolding protiens to concentrate, organize, and functionlly modulate signalling molecules
What are caveolinopathies?
class of muscle diseases associated with mutations in the human caveolin-3 gene. They include hyperCKemia (HCK), distal myopathy (DM), rippling muscle disease (RMD), and limb-girdle muscular dystrophy type 1C
why might mutations in caveolin lead to disease states?
Caveolin-3 interacts with a number of signaling molecules at the plasma membrane of skeletal muscle cells
Describe the morphology of an early endosome.
The early endosome invaginates forming?
multivesicular bodies (MVBs)
What changes take place as the endosome gets farther away from the plasma membrane?
the endosome becomes more acidic and then matures into lysosome
What is vesicle fusion mediated by?
SNAREs, Rabs (small Gs) which are important for correct destination
What type of pumps are found on lysosomes and endosomes?
Vacuolar (V)-Type ATPases that acidify lysosomes and endosomes
Describe the components of the V Type ATPase
V0 transmembrane
V1 ATPase domain like ATP synthase
What is the action of V type ATPases?
use energy of ATP hydrolysis to pump protons into lysosome
What are the 3 fxns of V type ATPases?
1 promote ligand-receptor dissociation (separage LDL from LDL-R by acid)
2.acivates lysosomal hydrolases
3.H coupled transport of other molecules
What happens during LDL-R endosomal sorting?
-LDL binds to LDL-R in clathrin coated pits
-LDL-LDLR internalized, sheds coat and fuses with early endosome
-the pH of the endosome causes dissociation of LDLR from LDL and LDLR is recycled to pmembrane
-LDL endosome invaginates to become MVB that moves along MT
-MVB's mature into late endosome
-Late endosome matures to lysosome and LDL is degraded and cholesterol is released
What do MVB's do?
digest non-recycled plasma membrane lipids and proteins
Proteins destined for MVB's are tagged with what?
mono-ubiquitin tag
What must take place w/n MVBs to achieve complete digestion of endocytosed membrane proteins?
allows hydrolase access to cystosolic domains of transmembrane proteins
Down regulation of EGFR and beta-AR is accomplished by what?
MVB-Lysosome fusion
What is the overall job of adaptins?
to target cargo to intracellular domains
Besides, adaptin, what do clathrin-coats require to assemble?
clathrin-coats require small G protein activity to assemble: ARF
AP1, AP3 and GGA do what?
direct cargo from golgi to lysosome or endosome
AP2 does what?
re-directs mis-directed receptors from plasma membrane to endosome
when you see corneal clouding think what?
What are the principal sites of intracellular digestion?
membrane-enclosed organelles that control the digestion of macromolecules
What is the common feature of lysosomal morphology?
high content of hydrolytic enzymes
Explain the 3 digestive fxns of lysosomes.
1. brkdn of intra and extracellular debris, old orgnalles
2 destroy phagocytosed microorganisms
3.results in production of cell nutrients
How are the acid hydrolases found in lysosomes synthesized?
as pro-enzymes that are enzymatically active at 5.0
What components makeup the lysosomal membrane?
protein-rich membranes (LAMP/LIMP family of glycoproteins for protection)
lyso-bisphosphatidic acid to protect lysosomal lipds from lumenal lipases
What acts as a lysosomal marker?
lyso-bisphosphatidic acid
Describe autophagy.
organelles that are not useful anymore are enclosed by membrane fragments from the ER forming autophagosomes
What form of lysosomes fuse of the membrane of the trans gogli? What start are they in?
primary lysosomes
inactive and empty
When are lysosome active?
when they are 2ndary: after they fuse with other lysosomes or endosomes
What targets lysosomal hydrolases to the lysosome?
M6P, targeting signal for lysososmes
Where is the lysosomal enzyme phosphorylated?
in cis golgi by M6P
What happens to the lysosomal enyzme tagged with M6P in the trans golgi?
binds to M6PR's which are bound to adaptins and then directed into vesicles coated with clathrin
What happens after the vesicle with the lysosomal hydrolases fuse off trans golgi?
the clathrin coat is removed and the uncoated vesicle fuse with late endosomes (low pH)
Low pH of endosome causes dissociation of enzymes from M6PR's
M6PR is recycled to membrane
Once the M6PR is dissociated from the hydrolases, what prevents the hydrolases from returning to golgi with R?
the enzymes are de-phosphorylated
What p-lates mannose residues on lysosomal enzymes?
GlcNAc (N-acetylglucosamine) phosphotransferase in cis-golgi
What cleaves GlcNAc?
phosphodiesterase leaving M6P on lysosomal enzyme
I-cell disease is a form of what?
mucolipidosis (lysosomal storage disease)
what is the problem in I cell disease?
enzymes not tagged in golgi by GlcNAc therefore enzymes NOT sent to lysosomes and now you have enzymes found in the cytoplasm and stuff in lysosomes NOT degraded (buildup of sphingolipids, glycoproteins, proteoglycans)
What is Hurler's Disease?
mucopolysaccharidosis (Type I)
Iduronidase deficiency
corneal clouding
affects dermatan sulfate and heparan sulfate degradation
Most common sphingolipidosis?
Gaucher: def in glucocerebrosidase
Tay Sach's is under what category of disease?
What enzyme are you lacking in Tay sach's?
hexoseaminidase A (hex A)
What accumulates in Tay-Sach's?
GM2 Ganglioside due to lack of lysosomal enzyme needed for breakdown
Characteristics of Tay Sach's?
progressive weakness
progressive motor and mental deterioration (b/c gangliosides are abundant in nerve cells thus Tay-Sach's kids have nerve cells swollen w/ lipid filled lysosomes)
How does T. cruzi enter cells?
via lysosomes (bypasses phagosomes)
attaches to host cell integrins causing increase in intracellular Ca that attracts lysosomes to plasma membrane
What does a lysosome become if it can no longer degrade material?
residual body that either expels materials from cell or becomes a lipofuscin granule that contains colored, autofluorescent lipids
T. cruzi causes what?
Chagas disease
The T. cruzi parasite secretes what?
trans-sialidase to remove the sialic-acid from lysosomal glycoproteins and pore-forming toxin, listeriolysin O that lyses the membrane releasing parasite into cytosol
What do skin melanocytes produce and store in lysosomes?
pigments that can be exoctyosed and taken up by keratinocytes leading to normal skin pigmentation
What do increased levels of free cholesterol result in?
decrease in HMG CoA reductase
stimulation of ACAT for storage of cholesterol
decrease syn of LDLR
and increase in 7-alphahydroxylase activity in liver to convert cholesterol to bile
Describe mitochondrial structure.
distinct outer and inner membranes
cristae, membrane invags (tubular or lamellar)
What is the fxn of cristae in mitochondria?
increase membrane surface area
also the location of ATP synthesis enzymes
What is contained in the matrix/mitosol?
mt DNA, mt ribosomes, enzymes of oxidative metabolism
Do most cells have tubular cristae or lamellar?
lamellar cristae is in most cells (liver cell, skeletal muscle, kidney)
What cells have tubulae cristea?
steriod secreting cells
describe the permeability of the outer mt membrane vs/ inner membrane?
outer:permeable to small molecules and ions
inner: impermeable to small, charged/polar molecules
What important processes take place in the outer mt membrane?
fatty acid elongation
fatty acid desaturation
phospholipid synthesis
What important processes take place in the inner mt membrane?
electron transport
oxidative phosphorylation
fatty acid transport
what important process take place in the mt matrix?
PDH complex
citric acid cycle
glutamate DH
fatty acid oxidation
urea cycle
What is Barth's syndrome?
X-linked cardiolipin synthesis disorder
Describe the structure of the outer mt membrane.
50% protein
porins beta sheet rich
receptors for proteins
location for phospholipase A2, monoamine oxidase, and acetyl CoA synthetase
What enzymes can be found in the outer mt membrane?
acetyl CoA synthetase
phospholipase A2
monoamine oxidase
Where do you find VDACs (voltage dependent anion channels)?
VDACs are found in the outer mt membrane that are beta sheet rich and allow small molecules through nonspecific water-filled central pores
What is the structure of the inner mt membrane?
75% protein 25% lipid
hight amt of cardiolipin
What is the fxn of cardiolipiin?
it is synthesized in Mt and used to form tight, permeability barrier to all polar molecules
-provides osmotic stability to membranes
-normal levels reqd for optimal bioenergetic fxns
In what type of cells would you see decreased levels of CL?
in cells undergoing apoptosis, aging and in Barth's syndrome fibroblasts
children that suffer from Barth's syndrome often die of what?
congestive cardiomyopathy or overwhelming bacterial infxns
How will the mt of a Barth's patient look?
bizarre with stacked or whorled layers of cristae
What connects the inner and outer mt membrane?
MPTP mitochondria permeability transition pore that is usually closed that is activated by increased matrix Ca or reactive oxygen species
What happens if the MPTP opens all the time?
mt become leaky, H ions enter, and ATP levels decline and cell dies by necrosis
When is necrosis cell death initiated?
when the cell is depleted of ATP
When is apotosis cell death initiated?
when MPTP opens but not long enough to deplete ATP..apoptosis requires ATP to happen thus there still needs to be ATP around
What are the components of the MPTP?
VDAC form outer pore component
Adenine nucleotide transporter (mt inner memb)
cyclophilin D: proline isomerase in matrix
Binding of pro-apoptotic factors to VDAC enables release of what?
cyt C that activates proteolytic zymogen cascade of caspases
Why is it important that inner mt membrane be impermeable?
to necessitate mt shuttles: adenine nucleotide exchanger, citrate shutte, ADP-P antiporter, carnitine shuttle
Proteins targeted to mt are synthesized where?
on cytosolic ribosomes
What aa are part of the zip code that transports proteins to mt?
basic aa targets proteins to outer matrix transport receptors
What do precursor proteins destined for mt bind to?
chaperone proteins, mt-import stimulating factor (MSF) and cytosolic Hsp70
What do the chaperone proteins do to the precursor proteins destined to mt?
hydrolyze ATP to provide energy to keep proteins unfolded, reqd for transport
Describe protein import into mt matrix.
MSF/Hsp70 binds to TOM R on outer membrane
TOMs recognize matrix targeting sequence
precursor is translocated across inner memb via TIM proteins require e chem gradient
signal seq is removed by matrix protease
What do TIM proteins require?
e chem gradient
Are proteins that are transported into the mt matrix spontaneously refolded?
yes or use chaperone Hsp60 and ATP hydrolysis to refold
Where are mt typically localized?
near sites of high ATP utilization (think cardiac muscle and sperm tail and eye: most highly aerobic tissue)
What typically does mt disfxn cause?
produces syndromes involving muscle and the CNS (including retina)
disruptions in oxidative metabolism affect highly aerobic tissues
What is a classical sign of mt disease?
observation of ragged red fibers in muscle indicates mt myopathy and too many mitochondria
How will a myofibril appear during mt myopathy?
irregular with crystalline, parking lot inclusions
Which parts of ox-phosphorylation produce most of endogenous ROS?
Superoxide is deleteriously produced as a byproduct of mitochondrial respiration (most notably by Complex I and Complex III by leaking electrons to oxygen
Where does the heat come from in non-shivering thermogenesis?
heat develops from trying to re-establish gradient to make ATP..lots of enzymes working but not very efficient b/c everything turned on full blast
What can ROS do to the ETC that can lead to disease?
build up of ROS can inactivate e-acceptors (degenerative diseases)
What happens to the oxygen that leaks from ETC and interacts with O2?
forms superoxide
superoxide is then converted by SOD to hydrogen peroxide which can then be reduced to water by catalase or to the dangerous hydroxide radical
How do ROS damage mt?
b/c mt have no histones they are less protected from radicals and therefore have less DNA repair
what antioxidants are present in mt?
SOD, catalase, glutathione
What does mt metabolism of ethanol lead to?
accumulation of NADH
Liver Mt involved in ethanol detox
What does the accumulation of NADH result in?
inhibition of gluconeogenesis leading to hypoglycemia and lactic acidosis
elevated NADH inhibits fatty acid oxidation and stim. fatty acid synthesis leading to fatty liver
Which organelle is thought to be endosymbiotic?
mt b/c of incorporation of bactera into ancient ancesterol cells
-they grow by fission, fusion and incorporation of plasma lipids, nuclear encoded proteins
-regulated by GTPases on Mt membranes
How many copies of the mt genome are within a single mt?
many copies
describe the mt genome.
ring of histone free DNA
12S and 16S rRNA, 22tRNA
multiple copies of DNA in clusters called nucleoids
no introns
what polymerase synthesizes new mtDNA?
DNA polymerase gamma
cell cycle replication in mt out of phase
What is the effect of exercise on mt?
increases size and number of mt and amt of oxidative metabolic enzymes
How are mtproteins inherited?
maternally inherited
and mutations 1st affect highly aerobic tissues such as nerves and muscles
What is the defective protein in LHON?
complex I NADH:CoQ
What happens in Leber's Hereditary Optic Neuropathy?
loss of central vision: defect in mtDNA
-person sees shadows
-affects primarily men in 20s and 30s
-most cases caused mutations in Complex 1, II and IV
-cause of blindness attributed to lack of ATP and damaged mtDNA that induces apoptosis
What is the fxn of the electron transport chain?
to produce an e-chem gradient that will power the ATP synthase to synthesize ATP
What is the fxn of Complex II of ETC?
not a proton pump. It serves to funnel additional electrons into the quinone pool (Q) by removing electrons from succinate and transferring them (via FAD) to Q
What is the overall "jist" of the ETC?
Energy obtained through the transfer of electrons down the ETC is used to pump protons from the mt matrix into the intermembrane space, creating an electrochemical proton gradient across the mt inner membrane. This electrochemical proton gradient allows ATP synthase to use the flow of H+ through the enzyme back into the matrix to generate ATP from (ADP) and inorganic phosphate. Complex I (NADH coenxyme Q reductase) accepts electrons from the Krebs cycle electron carrier NADH, and passes them to coenzyme Q (ubiquinone), which also receives electrons from complex II (succinate dehydrogenase). UQ passes electrons to complex III (cytochrome bc1), which passes them to cytochrome c (cyt c). Cyt c passes electrons to Complex IV (cytochrome c oxidase), which uses the electrons and hydrogen ions to reduce molecular oxygen to water
Explain where thermogenesis takes place.
thermogenesis takes place in brown adipose tissue that has lots of mitochrondria and lots of uncoupling protein, UCP (thermogenin) in inner mt membrane
What does non-shivering thermogenisis cause?
uncoupling of the e-chem gradient by inserting channels in membrane providing a path for H to leak from cytoplasm into matrix, short circuiting ATP synthase (uncouples e-transport chain from ATP synthase)
What is the primary fxn of the sER?
detoxification: metabolism of xenobiotics, detox by enzymes in sER
compare the morphology of sER with rER.
sER: interconnected network of tubules;tree-like structure'no bound ribosomes
rER: oriented stacks of flattened cisternae; bound ribosomes
What might cause the sER to grow?
sER increases significantly as secretory plasma B cells stimulated to secrete Igs
sER increases when stimulated to synthesize and secrete lipids/sterols, or to fxn as Ca repository
OUTSIDE influences: hep C virus or TX with statins
Which cells have ER?
all eukaryotic cells except enucleated RBC and sperm
What does the transitional ER contain?
ER exit sites: vesicles bud off for golgi
What are the 5 fxns of sER?
1. new lipid synthesis for cell membranes
2.synthesis of cholesterol; and conversion to steroid hormones
3.glycogen breakdown
4.calcium storage
5.detox of xenobiotics
What is reformed in intestinal epithelial cell sER?
TAGs and cholesterol esters that form chylomicron lipid droplets
sER cytosolic face re-esterifies fatty acids into TAGs b/c synthetic enzymes are located in ER
Where are nearly all classes of lipids synthesized?
Where does phospholipid syn occur?
in cytosolic leaflet of sER
What enzyme equilibrates phospholipids b/n the 2 leaflets of the ER bilayer?
What is the action of scramblase?
equilibrates phospholipids b/n 2 leaflets of the ER bilayer...enzymatically distributes phospholipids in a SYMMETRICAL manner
How are ER scramblases different from p. mem flippases?
scramblase: random, symmetrical
flipase:specific, asymmetrical
Do phospholipids flip/flop b/n leaflets of ER?
no..they are enzymatically distributed
Why are sphingolipids always on the outer leaflet of the plasma membrane?
b/c they are modified(sugars added) in lumen of golgi and transported to outside of p. membrane (outerleaflet)
Why is ceremide exported to golgi?
for sphingomyelin and glycolipids biosynthesis
Where does the first step of cholesterol syn occur?
Induction of HMG CoA Reductase affects sER how?
increases sER
What is the rate limiting enzyme for steroid biosyn and where is it located?
located in mt
What does a crystalloid ER indicate?
ER is found in sterol-secreting cells (leydig cells) Appear hexagonal
What is the fxn/location of glucose 6 phosphatase?
G6P ase located in sER membrane and acts to further breakdown glycogen: breaks glucose 6-P into P and glucose (controls glycogen metabolism)
**G6Pase is absent from most other tissues except liver
What are the structure and integrity of sER dependent upon?
lumenal free Ca--loss of ER lumenal Ca results in ER fragmentation. therefore, specific regions of sER STORES ca
What binding proteins facilitate Ca storage in ER lumen?
muscle= calsequestrin
most other cells=calreticulin
What is the problem in malignant hyperthermia?
RyR defect in T-tubules of SR leading to increased Ca causing increased body temp
which phase in drug metabolism does the CYP450 enzymes belong?
Phase 1: CYP450 oxidases attach oxygen to toxins to make them more soluble
How does the induction or inhibition of CYP450 enzyme levels affect drug metabolism
INDUCTION of CYP450 reduces drug effects: barbituates stimulate 3A4 family

INHIBITION of CYP450 increases drug effects:erythromyocin inhibtis 3A4 family
What is the action of CYP450:cyp3A4 family
metabolize more than 50% of all drugs by making insolule drugs that would stay in cells soluble by adding oxygen to them..increasing their solubility so they can be excreted
If you are giving a drug to a person that is on erythromiocin what will happen?
drug will last 2x as long, b/c erythromyocin inhibits 3A4 family
what is the hallmark sign of someone that has mixed acetominophen with alcohol?
extremely high transaminase levels (AST high) that decrease radidly by 50% in 1st 24hrs after presentation
Where is the MEOS (microsomal ethanol oxidizing system) located?
it is INDUCED under conditions of elevated cellular alcohol levels
What CYP metabolizes acetominophen?
What induces CYP2E1?
ethanol! therefore when you drink you have high levels of CYP2E1..if you take Tylenol it will be metabolized by the CYP2E1 leading to accumulation of ROS: NAPQ which is highly toxic to liver tissues
What does the generation of ROS in liver tissues lead to?
oxidative stress, reduction in NADPH, oxygen debt and liver toxicity
What enzymes are found in particular high concentrations in the PEX?
oxidases, catalase
What disease is associated with excess xanthine oxidase activity?
What is an important inhibitor of xanthine oxidase?
allopurinol to prevent gout
Where do PEX come from?
also called microbodies
similar to plant glyoxysomes
most abundant in LIVER cells
What type of molecules cause PEX to proliferate?
high fat diets, thyroid hormones, ethanol and diabetes
What is the fxn of peroxisomes?
generate and destroy hydrogen peroxide
principal organelle for fatty acid oxidation
purine degradation
Describe morphology of PEX.
single membrane
DO NOT have crystals
**pH optimum of 7.5 even though they fxn similar to lysosomes (pH 4.5)
What is the fxn of catalase in peroxisomes?
breaks down hydrogen peroxide to water
What is the action of glutathione peroxidase (GPX)?
degrades hydrogen peroxide to oxygen and water
what is the principal organelle for fatty acid oxidation?
PEX: degrades VLCFA like phytanic acid from plants
mt: degrades long chain FA
In the degradation of VLCFA in PEX, how is the energy released?
as heat
ATP NOT produced
get small acetyls which can then be used for cholesterol synthesis
What are nucleic acid purine moities degraded to?
uric acid
What do PEX synthesize?
plasmalogens-membrane compnents in brain, and heart
bile acids
what is a plasmalogen? what does a deficiency in it cause?
fatty alcohol with ether linkage (makes up large majority of myelin)
deficiency causes profound abnormalities in nerve cells myelination
What is a classic sign of PEX problem?
decreased plasmalogen levels
where do peroxisomes bud from?
PEX bud from ER and require pH optimal 7.5
lysosomes bud from trans golgi and require pH optimal 4.5
How do pex divide?
by fission but since they lack dna and ribosomes and have a single membrane they are quite different than mt
What are the 2 signal sequences for targeting to pex ?
SKL:PTS1 (Ser, Lys, Leu) that is NOT cleaved once protein inside
PTS2 IS that is cleaved once protein inside
they bind to different trasport carriers
Is PTS1 a C terminal tripeptide or an N terminal ?
c terminal
Does the import process of protein to PEX require ATP?
and recycling of R back to cytosol does as well
What are PPARs?
peroxisomal proliferator-activated receptors including RXR, RAR DIMERizing nuclear R's that act as TF's
How are many xenobiotics peroxisome proliferators?
they increase peroxidizing organelles by binding to PPARs
action of PPARalpha?
promote hepatic fatty acid oxidation during fasting-lowers total and HDL cholesterol
What is the action of PPARgamma?
enhances fatty acid storage under anabolic conditions: diabetes
What is the action of PPARbeta/gamma?
cell growth and differentiation via lipid metabolism
what are some of the symptoms of peroxisomal biogenesis disorders? of Zellweggers in particular?
increased phytanic acid and VLCFA
severe neurological and hepatic disfxn
deficient in plasmalogen sytnthesis
lack of peroxisomes "peroxisomal ghosts"
Note the difference b/n classic Refsums and infantile Refsums.
they are BOTH phytanic acid storage diseases (show elevated phytanic acid), but ONLY infantile shows elevated VLCFA and pipecolic acid
Infantile:PEX biogenesis disorder
Classic: single enzyme deficiency
what indicates pex biogenesis disorder?
empty or no peroxisomes
How are types A and B of peroxisomal disorders determined?
by clinical phenotype NOT genetic phenotype since mutations in any of several import proteins may cause either A or B therefore can't do amniocentesis
what is the problem with Group A and B PEX disorders?
trouble making fxnl PEX
inability to transport proteins in (due to either PTS1 or PTS2)
what is the cause of X linked ALD?
single enzyme deficiency
defective transporter for uptake of VLCFAs into PEX therefore accumulation of VLCFA
How does X-ALD differ from peroxisomal storage diseases?
unlike Zellwegger, X-ALD is due to single enzyme defiency rather than biogenesis disease
What is the age of onset of childhood X-ALD?
7 years with rapid deteriration and death in 2 yrs
most devastating form X-ALD
Describe the general properties of ECM
gel-like matrix composed of GAGs, proteoglycans, structural proteins, adhesive proteins
Main cell: fibroblasts
How does the ECM determine physcial properties of teeth, corneal stroma, tendons?
teeth and bone: calcified
corneal stroma: transparent
tendons: rope-like
What are the fxns of ECM?
scoffold to stabilize physical structure
influences cell behavior, survival, development, migration, prolif, shape and fxn
How is the ECM organized?
into fibers and ground substance
fibers: collagen, elastin, fibrillin
ground substance: highly hydrated gel of proteoglycans and glycoproteins
where will you find collagen in body?
25% of all proteins are collagens
tendons, skin, teeth, corneal stroma
what is collagen excreted from fibroblasts as?
pro-collagen and then it is cleaved to become collagen and assemble into fibrils
what is the formation of collagen?
triple helix
do both elastin and collagen get hydroxylated with both proline and lysine?
only collagen hydroxylated with lysine
both with proline
what reinforces collagen fiber formation?
covalent intra and inter molecular bonds formed by reactive lysines and/or hydroxylysines that strenghten collagen fiber
What are the 3 collagen families?
FACIT: fibrillar associated collagens
Sheet (network)-forming collagens
what types of collagen are fibrillar?
types I, II, III, V
associated with proteoglycans
what types of collagen are FACIT?
connecting or anchoring
VI binds and links type I fibrils
What types of collagen are sheet forming collagens?
which collagen type acts like a box spring?
type IV forming basal lamina
How are FACIT collagens different?
more flexible than fibrillar
help associate collagen fibers with proteoglycans/gags
bind surface of fibrillar collagens
Binding of FACIT collagens to fibrillar collagens leads to what type of organization in tendons vs. corneal stroma?
tendons: parallel bundles aligned along major axis of tension
corneal stroma: collagens cross at 90 angles
classic characteristics of patient with Marfan's?
pectus excavatum
aortic root dilatation
long limbs
what is the fxn of elastin?
allow elasticity and resilence
what is the dominant ECM proteins in arteries?
How is elastin different from collagen?
both have high amts of proline and glycine, but elastin is not glycosylated and has no hydroxylysine
what enables elastin to form fiber and sheets?
covalent crosslinking
what is the fxn of fibrillin?
binds to elastin and is essential for assembly and integrity of elastic fibers
Marfan's syndrome is a result of?
mutations in fibrillin gene
what is the tx for marfan's?
beta-AR blockade reduces risk of aortic dissection
what are GAG's?
very long chains of highly negatively charged repeating disachharides
Hyaluronan is a form of what?
what is its structure?
repeating sequence of 25,000 NONSULFATED disachharides which is unusual
what is unique about Hyaluronan from other gags?
it is non-covalently linked to core protein
synthesized by enzyme on cell surface
where would you find hyaluronan?
lubricant of joint fluid
vitreus humor of eye
acts like "hydrolics" by resisting compressive forces in tissues and joints
Describe the structure of the vitreous humor of the eye.
vitreous is a fiber-reinforced composite material
almost completely water
collagen fibers suspended in hyaluronan
proteoglycans bridge to collagen but held apart by hyaluronan
describe the structure of preteoglycans
core is formed by hyaluronic acid but proteoglycan proteins are associated w/ hyaluronic acid thru link proteins
Looks like a centipede