EXAM 2 Flashcards
1
Q
Glycolosis
A
catabolic pathway universal to virtually all organizsm. involves a series of enzyme catalyzed reactions within the CYTOSOL which phosphorylate, modify and split 6-carbon glucose molecule to eventually produce 2 molecules of 3- carbon pyruvate. ATP is consummed but overall gain is 2 ATP Key pathway for metabolsim of carbohydrates
2
Q
how does glucose go from blood to cell?
A
via specific glucose transporter protein GLUT1. this is a pssive glucose transporter that does not involve a coupled mouvement of any other ion or molecule
3
Q
how does glucose transport differ in the gut?
A
in gut epithelial cells the transport is an active mech coupled with the co-transport of Na+ using the existing Na-gradient to drive glucose from the gut lumen into the cell lumen against the concentration gradient of glucose
4
Q
Where does glycolosis occur?
A
cytosol of all tissues
5
Q
what happens to glucose once it passively enters the cell?
A
it is rapidly phophoylated at the 6-th position by HEXOKINASE( or glucokinase)
6
Q
what 4 pathways can the phosphorylated glucose enter?
A
1-glycolytic pathway( oxidation to provide energy-leads to formation of pyrvate)
2-pentose phosphate pathway( Oxidation, to produce cytosolic reducing power for synthesis, nucleotides or energy)
3-glycogen synthesis pathway(to store glucose for utilization at another time)
4-Synthesis of complex polysaccharides(cell matrix and cell wall polysaccharides)
7
Q
why is glucose phosphorylatd
A
1- to trap glucose within the cell(hence permit more glucose to passively diffuse in)
2-conserve energy:the phosphate that is donated to glucose from ATP will be used to regenerate ATP
3-“Tagging” of glucose all the glycolytic pathway intermediates are phosphorylated; the enzymes of the pathway recognize only these phosphorylation derivatives
8
Q
what enzymes phosphorylate glucose?
A
Hexokinase- most tissues, non specific, low Km(0.1mM) product inhibited( Glucose-6-phosphate)
2- GlucoKinase:only liver, glucose specific. high Km(10mM) no product inhibition(not saturated nor does build-up of its product reduce its activity there for it can continue to phosphorylate the excess glucose and remove it from the blood)
9
Q
what are the 2 phases of glycolosis?
A
the energy investement phase( cleavage of hexose chain) and the energy pay off stage
10
Q
steps of phase 1 glycolysis?
A
reaction 1: phosphorylation of glucose =the first ATP INVESTEMENT (hexokinase)
Reaction 2: Glucose-6-phosphate conversion to fructose-6-phosphate=isomerization of glycose-6-phosphate (phophohexose isomerase)
Reaction 3: fructose 6 phosphate phosphorylation to fructose 1,6-biphosphate= the second ATP INVESTEMENT (phophofructokinase)
Reaction 4: cleavage of fructose 1,6-biphosphate=production of 2 triose phosphates( aldolase)
Reaction 5: triose phophate interconverstion= isomerization of dihydroxyacetone phosphate ( triose -phosphate isomerase)
11
Q
what is the outcome of the 1st phase of glycolysis?
A
energy is invested in the form of 2 ATP per molecule of glucose the 6 carbon glucose molecule splits into two 3-carbon molecules of glceraldehyde 3 phosphate
12
Q
what occurs in the pay off phase of glycolysis?
A
Oxidative conversion of glyceraldehyde 3- phosphate to pyruvate and couplded formation of ATP and NADH
13
Q
what are the irreversable steps during the preparatory phase of glycolysis?
A
hexokinase reaction and the phosphofructokinase reaction. the PFK reaction is the committing step to glycolysis
14
Q
steps of phase 2 of glycolysis
A
Reaction 6: Glyceraldehyde 3 phosphate oxidation to 1,3-bisphosphoglycerate= generation of the first energy rich compound (glyceraldehyde 3 P dehydrogenase)
Reaction 7: phophate transfer from 1,3 bis phosphoglycerate to ADP= the first substrate level phosphorylation to PRODUCE ATP(phosphoglycerate kinase)
Reaction 8: 3- phosphoglycerate to 2- phosphoglycerate conversion=preparation for syntehesis of the next energy-rich compound(phophoglycerate mutase)
Reaction 9: Dehydration of 2-phophoglycerate conversion to phosphophenalpyruvate=synthesis of the second high-energy compound (Enolase)
Reaction 10: phosphoryl transfer from phosphoenol pyruivate to ADP= the second substrate level phosphorylation to produce ATP (Pyruvate kinase)
15
Q
how many molecules of ATP are formed from glycolysis
A
4 per molecule of glucose and 2 per molecule of glyceraldehyde-3-phosphate
16
Q
is the pay off phase of glycolysis reversible?
A
yes these reactions are substrate limited and can be easily reversed
17
Q
what enzyme catalyzes reaction 10 in glycolysis? is this reaction in equilibrium?
A
pyruvate kinase. reaction is far from equilibrium in cells and has a high driving force in the forward direction
18
Q
what is the significance of the energy levels of PEP hydrolysis?
A
it is almos 2 that for hydrolysis of the terminal phosphate from ATP, PEP has the highest phosphate transfer potential of any biological compund hance the energy from its hydrolysis is sufficient to easily drive synthesis of ATP from ADP with plenty of energy lef over to provide a substantial driving force in the forward direction
19
Q
why does PEP have such a high energy of hydrolysis?
A
because the initial product of PEP hydrolysis is enol-pyruvate which is very unstable and spontanesously froms the Keto-form
20
Q
what is the other high energy phosphate formed during the pay off phase of glycolysis at reaction 6?
A
glyceraldehyde 1, 3 biphosphate. this is an energy conserving reaction in which the energy of oxidation of an aldehyde to an acid is conserved by forming a high energy acyl-phosphate (50% higher energy provided by the hydrolysis of this compound than by ATP)
21
Q
what are the reactions in glycolysis that do NOT operate at equilibrium?
A
HK, PFK and PK
22
Q
what is the net production of glycolysis ?
A
2 ATP 2 NADH during the conversion of 1 molecule of glucose into 2 molecules of pyruvate
23
Q
what are the two metabolic fates of pyruvate?
A
1- entry into the citric acid cycle(via pyruvate dehydrogenase)
2-anaerobic reduction to lactate and the regeneration of NAD+( via lactate dehydrogenase)
24
Q
what is the fate of pyruvate in muscles cells during rigorous excercise ?
A
MADH from reaction 6 of glycolysis cannot be converted back. lack of NAD+ inhibits the reaction. so pyruvate will be converted into lactate(recution step coupled to the oxidation of NADH back to NAD+–> glycolisis can continue on and produce ATP without any net oxidation or reduction
25
what is ATP's effect on phophofructokinase in glysolysis?
ATP is an important negative allosteric regulator of the enzyme. high levels of ATP considerably increase the Km of the enzyme--> increase ATP in cell, decrease in glycolysis
26
what positively regulates activity of PFK?
ADP, AMP and fuctose 2,6 bisphosphate
27
what other carbohydrates can enter into glycolysis
fructose (through hexokinase)
Galactose (attached to UDP then epimerized to glucose)
Mannose *ophosphorylated by hexokinase then changed to fuctose-6-p by the action of phosphomannose isomerase)
28
what is the role of the Pentose Phosphate Pathway(PPP)
provides an alternative route to oxidation of glucose-6-phosphate
pahway yield NADPH which is usually used for reductive biosynthesis
NADPH protects agains oxidative damage due to O2 and H2O2
NADPH is used to recude oxidized glutathione(GSS)
29
what are the products of the Pentose Phosphate Pathway (PPP)
2 NADPH and ribose-6-phophate thei is called the oxidative phase
inthe non-oxidative phase-ribose-6-phosphate can be used for nucleotide syntehsis or recycled to glucose-6 phosphate(can go into glycolysis or PPP divison regulated by levels of NADPH in the cell)
30
how much glucose does the body need perday?
160 grams- of that 120 grams go to the brain
31
what is gluconeogenesis?
when glucose is depleted in fasting times there is the generation of glucose from non-sugar carbon compounds
32
which amino acids cannot provide carbon for glucose synthesis?
leucine and lysine
33
what are important glucose precursors for gluconeogenesis?
lactate pryuvate glyceral and amino acids
34
how are amino acids used for net glucose synthesis?
they are catabolized to pyruvate or intermediates of the citric acid cycle that can undrego oxidation to OXALOACETATE. bothy pyruvate and oxaloacetate are readily funneled into gluconeogenesis
35
where does glugoneogenesis take place?
mainly in the lliver some in renal cortex too and small intesting epithelial cells`
36
What happens to lactate produced in active muscle cells?
the lactate is transported to the liver and converted to glucose via gluconeogenesis then glucose is realeased to the blood and returns to the muscle where it is converted into glycogen (CORI CYCLE)
37
what occurs in gluconeogenesis?
pyruvate is converted into glucose
38
are glycolysis and gluconeogenesis the same but in opposite directions?
no, they do not have identical pathways. 7 of the 10 reactions of glycolysis which have very low free energy change and can be easily reversed and therefore are shared by both pathways
39
what are the 3 reactions in glycolyisis that are characterized by a large negative Delta G?
1- conversion of glucose to glucose-6-phosphate to fructose1,6-bisphosphate
2-phosphorylation of fructose-6-phosphate to fructose 1,6-biphosphate by phosphofructokinase-1
3-conversion of phosphoenol-pyruvate to pyruvate by pyruvate kinase
40
how does gluconeogenesis deal with the 3 irreversible reactions of glycolysis?
they are bypassed by a seperate sets of enzymes
41
what is the first reaction that is bypassed in gluconeogeneosis?
converstion of pyruvate into phosphoenolpyruvate(PEP) there are 2 alternative pathways from pyruvate to PEP, the path depends on the glycogenic precursor : pyruvate or lactate
42
what is the pathway in the first bypass when pyruvate is the starting material?
it is first transported from the cytososl into the mitochondria or is generated from alanine within the mitochondria by transamination.
pyruvate then is CARBOXYLATED to OXALOACETATE(4 carbons) at the expense of an ATP.
oxaloacetate is then REDUCED to MALATEmy (mitochondrial malate dhydrogenase) at the expense of NADH
MALATE exits the mitochondrion through a specific transporter in the inner mitochonrdial memebrane
in the cytosol it is OXIDIZED back to OXALOACETATE with production of cytosolic NADH(cytosolic malate dehydrogenase)
finally OXALOACETATE is DECARBOXYLATED to PEP by phosphoenolpyruvate carboxykinase ( this is an MG2+ dependat reaction and requires GTP as a phosphoryl group donor)
43
what does the dexacroxylation of oxaloacetate to PEP require?
phophoenolpyruvate carboxykinase. this is an Mg2+ dependent reaction and require GTP as the phosphoryl group donor
44
what is the signification of the oxidisation of malate back to oxaloacetate in the cytosol?
leads to the production of cytosolic NADH from NAD+. as a resullt NADH "shuttled out" from mitochondrion without crossing the memebrane to be used later in gluconeogenesis
45
what is the overall reaction of the bypass of pyruvate kinase starting with pyruvate?
Pyruvate+ATP+GTP+HCO3--->PEP+ADP+Pi+CO2 (Delta G=0.9kj/mol)
46
how is the first bypass reaction from pyruvate irreversible?
it is actually very negative because PEP concentration is low due to its consumption in other reactikon. so this reaction is effectively irreversible in the cell
47
what is the bypass reaction of pyruvate kinase when lactate is the starting material?
OXIDATION of lactate to pyruvate in the cytosol of hepatocyte by lactate dehyrogenase is accompanied by the production of NADH.
this reaction provides sufficient amount ot cytosolic NADH for gluconeogenesis so there is no need to"shuttle" NADH from the mitochonrdia
after produced pyruvate is transported to the mitochonrdia it is CARBOXYLATED to OXALOACETATE pyr pyruvate carboxylase at the expense of ATP
this OXALOACETATE is DECARBOXYLATED to PEP inside the mitochondria by mitochondrial PEP carboxykinase and PEP is transported from the mitochondria into the cytosol to continue on the gluconeogenic path
48
where is lactate produced?
erythrocytes or anaerobic muscle
49
how is the reaction of phosphofructokinase-1 bypassed in gluconeogenesis?
the second reaction that cannot be utilized in gluconeogenesis is the PHOSPHORYLATION of fructose-6-phosphate by phosphofructokinase-1 PFK 1
it is bypassed by the mg2+ dependent fructose 1,6-bisphosphatase which promotes the essentially irreversible hydrolysis of the C-1 phosphate
these 2 opposite reactions are catalyzed by different enzymes and are entirely different
Fructose1,6-bisphosphate_+H2O--> Fructose6-phospphate+pi (-16.3 kJ/mol)
50
what is the 3rd by pass and how is it done?
the 3rd irreverisble reaction is the bypass of hexokinase
the bypass reaction , the DEPHOSPHORYLATION of glucose 6-phosphate to yield glucose is catalyzed by glucose6-phosphatase
glucose 6-phosphatate+H2O-->glucose+Pi
the Mg2+ dependant enzyme is located on the inside surface of the ER of hepatocytes and renal cells (muscle and brain tissue dont have this enzyme there for they are dependnt on the outside supply of glucose delivered through the bloodstream)
51
what is the overall reaction of gluconeogenesis?
2 pyruvate+4 ATP+2 GTP+2NADH+2 H+ +4 H2O--> glucose+ 4 ADP+ 2 GDP + 2 NAD+ +6 Pi
52
how do cells assure the irreversibility of glyconeogenesis?
this is an expensive process and much of the high energy cost is necessary to ensure the irreversibility of gluconeogenesis
53
what is the first control point in gluconeogenesis?
this first congtrol point determines the fate of pyruvate in the mitochondria
Acetyl-CoA is a positive allosteric moedulator of pyruvate carboxilase and a negative modulaor of pyruvate dehydrogenase
accumulation of Acetyl-CoA means the cells needs are met- it inhibits pyruvate dehydrogenase, slowing formation of acetyl-coA from pyruvate and sitmulates guconeogenesis by activating pyruvate carbozylase
54
what is the second control point of gluconeogenesis?
irreversible conversion of furcotse 1,6 bisphophate to fuctose 6-phosphate catalyzed by the fructose 1,6-bisphosphatase-1(FBP-1) the corresponding glycolytic reaction is catalyzed by a diff enzymes phosphofuctokinase-1(PFK-1)
simultaneous operation of both enzyme would consume ATP wihtout accomplishing any chemical or byological works, futile cycle.
to avoid this they are regulated in a coordinated and reciprocal manner allowing only one proces to be active at a time
AMP inhibits FBP ase-1 and stimulates PFK-1
PFK-1 is also stimulated by ADP but inhibited by citrate and ATP
all changes regulated by rapid allosteric mech
55
What are the regulatory processes triggere from outside the cell for glycolisis and gluconeogenesis?
by hormones insulin and glucagon
the hormonal regulation of both pathways is mediated by FRUCTOSE 2,6- BISPHOSPHATE (F26BP). its in allosteric mediator that stimulate PFK-1 and inhibitse FBPase-1--> stimulates glycolysis and slowing gluconeogenesis
56
how are levels of Fructose 2,6-bisphosphate (F26BP) regulated?
it is formed by the phosphorylation of furctose 6-phosphate catalyzed by phosphofructokinase -2 (PFK-2 and is borken down by fructose 2,6 bisphosphatase-2 ( FBPase-2) they are regulated in a reciprocal fashion by insulin and glucagon
57
what effect does glucagon have?
glucagon stimulates liver adenylate cyclase to sinythesie cyclic AMP that acitvates CAMP dependant protein kinase phosphorylation of PFK-2/FBPase-2 protin this phosphorylation increases FBPase-2 activity and inhibits PFK-2 activity --> lowers F26BP levels and inhibits glycolysis and simulates gluconeogenesis
--> glucagon promotes release of glucose in blood
58
what is the effect of insulin in regulateing glucose levels?
insuline simulates the dephosphorylation of PFK-2/FBPase-2 by a phosphoprotein phosphatase.
--> inhibition of FBPase-2 and activation of PFK-2 that increases level of F26BP-->stimulates glycolysis
59
how does insulin regulate transcription?
insuline acts through its membrane receptor to turn on the signaling pathway resulting in the activation of prtoein kinase B(PKB)
in response to insulin the transcription factor FOX01 --> stimulates the synthesis of gluconeogenic enzymes PEP carbizykinase and Glucose 6-phosphatase
FOX01 leaves the nucelues and is phosphorylated by activated PKB then tagged by ubiquitin
60
how does glucagoneffect FOX01 activity?
glucagon prevents the phosphorylation of FOX01 by the activated PKB. FOX01 remains aftive in the nucleius
61
what is the first step of cellular respiration?
organic fuel molecules are oxidized to yield 2 carbon fragments in the form of acetyl group of acetyl group of acetyl-coenzyme A(Acetyl- coA)
62
what is the second step of cellular resipiration?
the activated acetyl groups( acetyl-CoA) are fed into the citric acid cycle which enzymatically oxidizes them to CO2 the energy released is conserved in the form of reduced electron carriers NADH and FADH2
63
what is the 3rd step of cellular respiration?
NADH and FADH2 are oxidized and the electrons they carry are transferred through the respiratory (electron-transfer) chain to )2 the final electron acceptor ruducing it to H2O. this electron flow drives the production of energy which is conersved in the form of ATP by a process called oxidative phosphorylation
64
what is the significance of the citric acid cycle?
the citric acid cycle is the final common pathway for the oxidation of fuel molecules - carbohydrates, fatty acids, and some amino acids (a hub metabolsim)
65
how does pyruvate enter the citric acid cycle?
pyruvate is converted into Acetyl- CoA by pyruvate dehydrogenase PDH complex. this complex catalyzes irreversible oxidative decarbozylation of pyruvate resulting in the remouval of its carboxyl group in the form of Co2 and formation of acetyl-CoA. this reactikon requires the sequentia action of three diferent enzymes E1 E2 and E 3 and 5 diff coenzymes
66
what are the enzymes of the PDH complex?
```
pyruvate dehydrogenase(E1)
dihydrolipoly transacetase(E 2)
Dihydrolipoyl dehydrogenase(E 3)
each are present in multiple copies in the complex
number of copies varies between species
eukaryotes ( 30 E1 and 12 E 3)
```
67
what are the co-enzymes in the PDH complex?
coenzyme A(CoA-SH)- reversibly associating coenzyme containing a reactive thiol-SH group that froms a thioester with acetate in acetyl-CoA
Nicotinamide Adenin Dinucleotide(NAD+): also a reversibly associating coenzyme it serves as an electron carrier
Thiamine Pyrophosphate(TPP) attached to E1 and serves as a catalytic cofactor
Lipoate: Attached to E2 through Lys of E2 and has 2 thiol groups that can undergo reversible oxidation to a disulfide bond it can serve both as an electron carrier and as an acyl carrier
Flavin Adenine Dinucleotide(FAD): attached to E3 it serves as an electron carrier
68
what is the reaction mechanism of the PDH complex?
step 1: pyruvate reacts with the bound TPP of pyruvate dehydrogenase(E1) undergoing decarboxylation to the hydroxyethyl derivative(2 carbons)
step 2: E1 trasnfers the acetyl group and 2 electrons from TPP to the oxidized form of the lipoyllysine of the core enzyme,dihydrolipyl transacetylase(E2)
step 3: in the reaction of transesterification the -SH group of CoA replaces the- SH group of E2 to yield acetyl-CoA and fully reduced form of the lipoyl group
Step 4: Dihydrilipoyl dehydrogenase(E3) promoes the trasnfer of 2 hydorgen atoms from the reduced lipoyl groups of E2 to the FAD porstetic group of E 3, restoring the eoxidized from of the lipoyllysyl group of E2
Step5: the reduced FADH2 of E3 transfers a hydride ion to NAD+ resulting in NADH
69
explain the "swinging arm" term?
the lipoamide of E2 provides the swinging arm that transfers the product of E1(the hydroxyethyl group) to the active site of E2 where it is oxidized to the acetyl group and trasnfered to CoA-SH
the swinging arm ins its reduced state then interacts with E 3 in order to regenerate its oxidized head group
70
why is the PDH complex an example of the tethering mechanism for the channeling of a substate between active sites?
1- diffusion of substrates and products between the enzymes is no required (increase in reaction speed)
2- the intermediates never leave the complex(increase in concentration and reaction speed)
3-other competing compounds are prevented from entering active sites( increase reaction fidelity)
71
where does the citric acid cycle take place?
mitochondria
8 steps in which the 2 carbon acetyl CoA is completely eoxidized to CO2 with most of the energy conserved in the form of NADH and FADH2
72
what is the 1st step of krebs cycle?
formation of citrate:
the reaction is catalyzed by citrate synthase
involved aldole condensation of acetyl-CoA with oxaloacetate to form citroyl-CoA which is then hydrolyzed to citrate and CoA
the hydrolysis of Citroyl-CoA pulls the overall reaction in the direction of citrate synthesis
the large negative Delta G is essential to the operation of the cycle due to the very low level of oxalacetate in the mitochondria
73
what is the 3rd step of the krebs cycle?
Oxidation of isocitrate to alpha Ketoglutarate and CO2:
the reaction is catalyzed by isocitrate dehydrogenase
this is the first OXIDATION reaction of the cycle it involved the transfer of electrons to NAD+ it is also a decarboxylation step with CO2 being released
there are 2 diff forms of isocytrate dehydrogenase one reuiring NAD+ as an electron acceptor occurs in the mitochondria and serves in the citric acid cycle the other can recognize NADP+ and is mainly used to make NADPH for reductive biosynthesis in the cytosol
large Negative delta G-imp REGULATORY STEP, rate of formation of alpha-ketoglutarate is imp in determining the overall rate of the cycle
74
what is the 2nd step of the krebs cycle?
Formation of isocitrate via cis-aconitate:
the reaction is catalysed by ACONITASE
the reaction involves remouval and addition of water dehydration-hydration
aconitase can promote the reversible additon of H2O to the double bond of cis-aconitate in 2 diff ways. one leading to citrate and the other to isocitrate however the reaction is pulled to the right beacuse the isocitrate is rapidly consumed in the next step of the cycle
large positive delta G but close to equilibrium in the cell because the product is kept at low concentration
75
what is the 4th step of the krebs cycle?
Oxidation of Alpha-Ketoglutarate to Succinyl-CoA and CO2:
the reaction is catalyzed by Alpha-Ketoglutarate dehydrogenase complex which is very semilar to the pyruvate dehhydrogenase compled. the mech is also very similar to that of the conversion of pyruvate to acetyl-CoA
this is the second coidation/dexarboxylation reactions of the cycle
NAD+serves as an electron acceptor and COA-SH is a carrier of the succinyl group
the reaction has a large neg G, REGULATED step
76
what is the 5th step of the krebs cycle?
Conversion of Succinyl-CoA to Succinate:
the reaction is catalyzed by Succinyl-CoA synthase or Succinic Thiokinase
this is the ONLY phosphorylation steop in the cycle that directly yields a high energy phosphjate bond. all other ATPs are gnerated indiretly through electron carriers and oxidative phosphorylation
GDP is phosphorylated to GTP , GTP is sued as a phosphoryl donor in protein synthesis and signal transduction or can easly be converted to ATP by nucleotide diphosphokinase
low Delta G-REVERSIBLE REACTION
77
what is the 6ht step in the krebs cycle?
Oxidation of succinate to fumarate:
the reaction is catalyzed by succinat dehydrogenase
this is the third oxidation reaction of the cycle
enzyme contains one molecule of covalently bound FAD it is tightly bound to the inner mitochondrial membrane and is directly linked to the electron transport chain. electrions pass from succinate through FAD and are fed directly into the chain resulting in the synthesis of ATP
Delta G of 0 REVERSIBLE
78
what is the 7th step in the krebs cycle?
Hydration of fumarate to malate:
the reaction is catalyzed by Fumerase
this is a hydration reaction
the reaction is close to equilibrium
79
what is the 8th step of the krebs cycle?
Oxydation of malate to oxylacetate:
the reaction is catalyzed by L-malate dehydrogenase
fourth oxidation reaction which produces oxalacetate and NADH and completes the cycle
large positive delta G but in the cell there is low concentration of oxalacetate which is continually remouved by the citrate synthase reaction hence is close to equilibrium
80
are the CO2 molecules released in the citric acid cycle from the Acetyl CoA?
no they are different (Co2 Relseasd in oxidation of isocitrate and alpha-Keto glutarate)
additianal turns around the cycle are required to relsease these carbons as CO2
81
how is the energy released by oxidations conserved?
the energy is conserved in the reduction of three NAD+ and one FAD and the production of one GTP
82
what is the overall reaction of the citric acid cycle?
acetyl-CoA+3NAD+ +FAD+GDP+Pi+2H20-->2 Co2+3NADH+FADH2+GTp+2H++CoA
83
what is the overall yield of ATP from the aerobic ocidation of one molecule of clucose to CO2
20-32 ATP per molecule
84
what is the amphibolic function of the citric acid cycle?
in aerobic conditions the citric acid cycle is an amphibolic pathway one that serves both the catabolic and anabolic processes
besides its role in the oxidative catabolism of carbohydrates fatty acids and ammino acidsthe cycle provides precursers for many biosynthetic pathways-->anabolic functions
85
wot whate AA can oxaloacetate and Alpha-Ketoglutarate serve as precursers respecitvely?
oxaloacetate=aspartate
| Alpha-Ketoglutrate=glutamate
86
What is an anaplerotic reaction?
this is how the interemediates that are remouved in the citric acid cycle to serve as biosynthetic precursors are replenished.
this reaction produces four carbon intermediates by carboxylation of 3 carbon compounds
87
what is the most important anaplerotic reaction in a mammalian liver and kidney?
thje reversibl carboxylation of pyruvate by CO2 to form oxaloacetate catalysed by pyruvate carboxylase
88
what inhibits the production of acetyl CoA by the PDH complex?
it is allosterically inhibited by high level of acetyl CoA, ATP and NADH
it is turned on by AMP, CoA and NAD+ and Ca+
in addition in mamels the activity of PDH is inhibited by reversible phosphoylation of one of the 2 subunits of its E1 component
89
at what steps is the citric acid cycle regulated?
it is regulated at its 3 exergonic steps
1-citrate synthase
2-isocitrate dehydrogenase
3-alpha-Ketoglutarate dehydrogenase complex
90
how does the regulation of citrate synthase occur?
it is inhibited by NADH ,succinyl CoA, citrate, ATP and stimulated by ADP
91
how is isocitrate dehydrogenase regulated?
it is inhibited by ATP and NADH stimulated by ADP and Ca+
92
how is the Alpha-Ketoglutarate dehydrogenase complex regulated?
inhibited by Succinyl-CoA and NADH and stimulated by Ca+
93
what is glycogen?
glycogen is readily mobilized storage form of glucose it is very large, bracnehd polymer of glucose residues linked together with alpha1-->4 and alpha1-->6 glycosidic bonds .branching occurs at about every tenth residues through the alpha1-->6 linkages and gives glycogen many ends and more compact structure. Glycogen can be broken down to yield glucose molesules when energy is needed
94
what are the major sites of glycogen storage?
storeed in large cytosolic granules, the two major sites of glycogen storage are the liver and skeletal muscle glycogen represents 1-2% of muscle weight and 10% of weight of liver
95
where is the most glucose stored?
because the total mass of muscle is much greater than that of liver , total glycogen stored in muscle is about twice that of liver
96
how long does muscle glycogen last?
it serves as aquick source of energy and can be exhausted in less than 1 h during vigorous activity
97
what is the purpose of liver glycogen?
liver glycogen serves as a reservoir of glucose for other tissues when dietary glucose is not available can be depleted in 12 to 24 h
98
compare glycogen pathways in liver and muscle
similar general mechanisms for storing and mobilizing but the enzymes differ in subtle yet important ways
99
what are the 3 enzymes for glycogen breakdown?
glycogen phosphorylase, glycogen debranching enzymes and phophoglucomutase
100
what is the role of glycogen phosphorylase in glycogen breakdown?
catalyses the remouval of a terminal glucose residue from the nonreducing end(end with a free 4'-OH of a glycogen chain
in this phosphorolysis reaction an Alpha 1-->4 glycosidic linkage between 2 glucose residues undergoes attack by inorganic phosphate(pi) reulting in the relseas of phosphorylated glucose ( glucose-1-phosphate)
energy conserving reaction since some of the energy of the glycosidic bond is preserved in the formation of a sugar phosphate without ATp hydrolysis
in contrast to glucose glucose 1-phosphate is ionized and cannot diffuse out of the cell( stays in muscle)
reptitive process until the enzyme reaches the 4th glucose unit from a branch point
101
what is the debranching enzyme's role in glycogen breakdown
this enzyme contains glucotransferase and glucosidase activities, catalyses the removal of branch points in 2 steps
1- the transferase activity of the enzyme shifts a block of 3 glucose residues from a branch to a nerby nonreducing end, to which they are reattached in an Alpha 1-->4 arm
2-glycosidase activity removes the single glucose residue remaining at the branch point resulting in free glucose and unbranched Alpha 1-->4 polymer which is a substrate for further glycogen phosphorylase activity
102
what happens to glucsoe 1- phosphate from the glycogen phophorylase reaction in glycogen break down?
it is converted into glucose6-phosphate in the reversible reaction catalysed by phosphoglucomutase . in muscle cells it enter glycolysis (energy source) . in the liver it is converted to glucose which is realeased into the blood(glucose source) this reaction is catalyzed by glucose 6- phosphatase which is absent from muscle and the brain
103
what is the role of the formation of UDP-glucose in glycogen synthesis?
glycogen is synthesized by a pathway that utilizes a sugar nucleotide: Uridine Diphosphate Glucose (UDP glucose)
UDP Glucose is formed in a condsnation reeaction btween a nucleotide triphosphate (Uirdine triphosphate) and a sugar phosphate(Glucose-1 phosphate) catalyzed by UDP-Glucose pyrophosphorylase
the reaction is pulled in the forward direction by the hydrolysis of pyrophosphate(PPi) to the orthophosphate (2Pi) by inorganic pyrophosphatase
UDP glucose is an "activated" form of glucose
104
how is the glycogen chain elongated?
a glycogen chain is elongated by the addition of new glucose residues in Alpha 1-->4 linkages to the nonreducing end of glycogen
the process is catalyzed by glycogen synthase which promotes the transfer of glucose residue from UDP-glucose to a non-reducing end of a branched glygocen molecule
Glycogen Synthase cannot initiate a new glycogen chain de novo
105
Can Glycogen Synthase be used to initiate a new glycogen chain?
noyou need a preformed Alpha 1--> polyglucose chain having more than four glucose residues
106
how does the initiation of a new molecule of glycogen occur?
Glycogenin a 37 kDa protein serves as the primer on which new chains are assemble and as the enzyme that catalyzes their assembly
107
what are the steps of denovo synthesis of glycogen
the synthesis of a new glycogen molecule begins with the transfer ofa glucose residue from UDP-Glucose to hydroxyl group of Tyr194 og glycogenin
the transfer is catalyzed by the intrinsic glucosyl-transferase activity of glycogenin
the nascent chain is extended by addition of 7 more glucose reisudes each derived from UDP-GLucose they are catalyzed by the chain extending activity of Glycogenin after that Glycogen synthase takes over further extending the glycogen chain
Glycogen synthase cannot make the Alpha 1-->6 bonds found at the branch points of glycogen
108
How is branch synthesis achieved in glycogen?
glycigen branching enzyme
the enzyme creates a new branch by cutting a terminal fragment of 6-7 glucose residues from a polymer at least 11 glucsoe residues long and transfering them to the C-6 hydorxyl group of an internal glucose residue
the biological effect of branching is to make the glycogen moleucle more soluble and to increase the number of nonreducing ends this increases the number of sites accessible to glycogen phosphorylase and glycogen synthase both which at only at nonreducing ends
109
where do glycogen phosphorylase and glycogen synthase act?
only at non reducing ends
110
how is glycogen synthesis and breakdown regulated?
to prevent futile cycling glycogen phosphorylase and glycogen synthase are reciprocally regulated by allosteric effectors that signal that energy state of the cell and by reversible phosphorylation which is responsive to hormones such as insulin epinephrine and glucagon( hormonal regulation)
Glycogen phosphoylases of liver and muscles are isozymes encoded by dufferent genes their regulations also differ
111
the activity of what 2 enzymes is regulated in order to regulated glycogen synthesis and break down?
Glycogen phosphorylase and glycogen synthase
112
How is muscle glycogen phosphorylase regulated?
consists of 2 subints and existes in 2 interconverable forms a(catalytically acive) b( inactive)
phosphorylase b is converted int oa more active phosphoylase b kinase by phosphorylation of its Ser 14 this is triggered by epinephrine which activates phosphorylase b kinase indirectly through a series of steps
Dephosphoryaltion of phosphorylase a with phosphorylase a phosphatase also called phosphoprotein phophatase 1(PP1) results in less active phosphorylase b
TWO ALLOSTERIC CONTROL MECHS:
1-Ca 2+binds to phosphorylase b Kinase and increases its activity
2-AMP binds to and activates phosphorylase b kinase, ATP blocks the allosteric site to which AMP binds, inactivating phosphorylase b kinase
113
how is glycogen phosphorylase regulated in the liver?
HORMONAL RECULATION: mech similar to that of the muscle enzyme(phosphorylation/dephosphorylation) however it is triggered by glucagon
ALLOSTERIC REGULATION: of the liver glycogen phosphorylase differs from that of the muscel glycogenphosphorylase in 2 respects: 1) AMP does not activate liver phosphorylase b 2) blood glucose inactivates active phosphoylase a by binding to an inhibitory allosteric site (glucose sensor)
insuline also acts indirectly to stimulate phosphorylase a phosphatase PP1 and slow glycogen breakfdown
114
how is the regulation of glycogen synthase done?
Glycogen synthase exists in 2 interconvertable froms a and b(inactive)
converstion of active glycogen synsthase a into inactive glycogen synthase b occurs by phosphorylation of three Ser residues near its carboxyl terminus
glycogen synthase can be phosphorylated by at least 11 different protein kinaases, most imp regulatory kinsase is glycogen synthase kinase 3(GSK3)
GSk3 can phosphorylate glycogen synthase only after another prottein kinase , casein kinase II CKII has phosphorylated glycogen synthase(primming)
conversion from b form to a frowm occurs by dephosphorylation with a phosphoprotein phosphatase PP1
HORMONAL REGULATION: insulin triggers acitvation of glycogen synthase b by blocking activity of GSK3 and activating PP!,glucagong and epinephrine trigger inhibition of PP1
glucose-6phosphate and glucose are allosteric regulators of glycogen synthase
115
what is Type 1 a glycogen storage disease
effects Glucose-6-phosphatase in the liver , symptoms are enlarged liver kidney falure
116
what are the symptoms of Cori's or forbes disease?
glycogen storage disease type IIIa
| effects debranching enzyme in liver skeletal and cardia muscle symptoms are enlarged liver in infants myopathy
117
Anderson's disease?
type IV glycogen storage disease effects branching enzyme in liver and skeletal muscle symptoms are enlarged liver and spleen myoglobin in liver
118
McArdle's disease?
type V glycogen storage disease effects muscle phosphorylase in skeletal muscle causes exercise-induced cramps and pain; myoblobin in urine
119
what are the enzyme in the first bypass of glucogenesis when pyruvate is the starting product?
pyruvate-->goess into mitchondria--> pyruvate carboxylase( Carboxylation ATP consummed)-->oxaloacetate-->mithocondrial malate dehydrogenase(reduction NADH used)--> Malate--> goes to cytoplasm-->cytosolic malate dehydrogenase (oxidation NADH relased)-->oxaloacetate-->cytosolic PEP carboxylase(Decarboxylation)-->PEP
120
whata re the enzymes in the 1st bypass reaction of gluconeogenesis if lactate is the starting product?
lactate--> oxidized to pyruvate in cytopolasm by lactate dehydrogenase(produces NADH , dont need to shuttle )-->in mithocondria pyruvate carboxylated to Oxaloacetate by pyruvate carboxylaze(costs ATP)-->oxalacetate is decarboxylated to PEP in the mitochondria by mitochondrial PEP carboxykinase
121
whatare the 3 main players of signal tranduction?
1- receptors- proteins at the plasma membrane that specifcially regognize extra celular signals
2- Trasnducers: proteins that decode the signals received from the receptors and transduce them to the cell machinery (ex G proteins)
3-amplifiers: enzymes or channels which catalyze the activation of secondary messengers that give rise to cellular responses
122
what are some examples of signal receptors?
hormones, neurotransmitters, growth factors, light, odors ,stress strain
123
what are some examples of amplifiers?
nucleotide cyclases, phospholipases, kinases and ion channels
124
are receptors transducers and amplifiers seperate molecules?
not necessarily can be built on one protein or each component can be a seperate molecule
125
what are the characizations of signal transduction incells
specificity
amplification- when enzymes activate enzymes the number of affected molecules increases geomtrically in an enzyme cascade
desensitivisation/adaptation- receptor activation triggers a feedback circuit that shuts off the receptor or removes it from the cell
Integration-integrate input from various receptors
126
what are the 4 classes of plasma membrane receptors?
receptor ionchannels(eg acetylcholine receptor)
Receptor enzymes( receptor tyrosine kinase and receptor serine/theronine kinases)
G-protein couple receptors(Beta adrenergic receptor)
Receptor guanylyl cyclases
127
what are the 3 kinds of receptors?
plasma membrane receptors
adhesion receptors
intracellular receptors
128
what are adhesion receptors?
interacte with mcaromolecular components of the extracellular matrix(such as collagen) and convey instructions to the cytoskeletal system about cell migration or adherence to matrix. Ex INTEGRINS
129
how do intracellular receptors function?
receptors are hydrophobic enough and small enough to pass readily across the target cell's plasma membrane
they directlyregulat the activity of intracellular proteins
major type is Steroid hormones they mainly reside in the nucleus
receptor/hormone complex interacts with specific"response sites" on the genome and regulate transcription of the responsive genes
130
what are the properties of an ion channel receptor?and an exampl
-membrane surface proteins
-receptors with intrinsic channel TRANSDUCTION and provides AMPLIFICATION of the response
best example is the nicotinic acetylcholine receptor:multisubunit integral membrane protein
specific binding site for acetylcholine and allows the passage of NA CA and K ions when open
opens transiently (via desensitization)
131
what are the 2 types of plasma memrane receptor enzymes?
- tyrosine kinases(insulin EGFR)
| - receptor serine/theronine kinases
132
what are the important domains on receptors tyrosine kinase?
ligand-binding domain on the extracellular suface of the plasma membrane
enyzmatic active site on the cytosolic site the 2 domains are connected by a single transmembrane segment
133
what is the trole of the cytoplasmic domain on receptor tyrosine kinases?
the cytoplasmic domain is the ligand bnding domain it phosphorylates Tyr residues ins specific target proteins
134
what are the main characteristics of the insuline receptor
membrane bound tyrosine kinase
2 monomers that form a dimer each monomer has an alpha and a beta subunit. binding o fthe insuline to the alpha subunit leads to KINASE ACTIVATION
each beta subunit then phosphorylates 3 critical Tyr residues near the COOH-terminus of the other beta subunit--> this AUTOPHOSPHORYLATION opens up the active site
the enzyme can then phospohylate Tyr residues of the majors subsrates in the cell(b/c the phosphorylated-Tyr bind to Ser honmology doman 2 (SH2) motifs present in diverse signaling proteins
135
how is cytosolic tyrosine kinase activated?
receptors that doe no have intrinsic tyrosine kinase activity once the ligand has bound to the receptor they can bind cytosolic tyrosine kinase
ex erythrocite formation in mamal the erythropeiotin(EPO). activation of EPO receptor binds and activates the soluble Tyr-Kinase JAK
JAK in turn phosphorylates several Tyr inthe cytoplasmic domain of EPO recetpor which initiates different signaling cascades
ex: the SH2 domain of transcription factor STAT5 binds to the phosph-Tyr of the EPO . phosphorylation of STAT5 by JAK results in its dimerization-this exposes its nuclear localization isgnal and targets the dimer to the nucleus. In the nuclesu STAT5 will turn on expression of EPO-regulated genes.
136
what is the basic mechanism of function of receptor serine/ threonine kinases?
these are either cytosolic or single transmembrane proteins with a ser/thr kinase domain on the cytosolic side o the plasma membrane . they DIRECTLY phosphorylate the latent gene regulatory proteins called Smads which then translocate to the nuclesu to activate gene transcription. there are 2 classes of Ser/Thr kinases type 1 and type 2 which are structurally similar and act as homodimers
137
what super family acts through receptor serine/theronine kinases?
the transforming growth factor-beta (TGF beta)they us ser/thr kinases and smads to regulate biological functions such as pattern development, cell proliferation, specification and differenctiation,extracellular matric production, cell death,tissue repair and immune rectulation
138
what are the 2 main subfamilies in the TGF beta superfamily?
the TGF beta or activin subfamily and the bonemorphogenic BMP subamily
139
where are most ser/thr kinase receptors found?
they are found mostly in the cytoplasm while ALL Tyr kinases are bound to the membrane (JAKs are bound by their association with cytokine receptors)
140
what is the paticularity of the G-rptoein couple Receptor(GPCR)?
they consist of 3 components: plasma membrane receptor wich seven transemembrane helical segements
a guanosine nucleotide-binding protein(G-protein) which acts as the TRANSDUCER
an enzyme in the plasma membrane that generates an intracellular second messenger and functions as the AMPLIFIER
large diversity, respond to many signals the target of 50% of drugs, involved in a lot of desease states
EX Beta Adrenergic receptor-regulats epinephrine effects "target of Beta blockers"
141
what is the final effect of G proteins?
they mediate signal transduction and provide sensitivity and specificity
142
what are the components of Heterotrimeric G-Proteins?
they are peripheral membrane proteins tightly boudn to the intracellular face of the plasema membrane whic are involved in plasma membrane signalling
they ahve 3 subunits: Alpha Beta and epsilon.
alpha subunit are fatty aceylate and tightly bound to the membrane- they can dissociate from the beta and epsilon entity, which always remain a single unit
alpha sub-units have enzymatic activity- they mind and hyrdrolyze GTP
143
what are the 4 steps of the G-protein Cycle?
G-protein cycle involves the exchange of GDP for GTP which results in the activation of downstream effector enzymes
1- Contact of the Alpha-subunit with the hormone-receptor complex causes displacemtn of bound GDP by GTP
2-The activated Galpha-GTP dissociates from the Gbeta epsilon-subints and interacts with an effector enzyme (adenylyl cyclase) increasing its activity
3-at the same imte that the effectors is activated, GTP on G alpha is hydrolyzed due to its intrinsic GTPase activity
4-the G alpha-GDP dissociates fromthe effector enzyme and returns to bindthe Gbeta and epsilon subunits so a new cycle can start.
G alpha-can sense if the receptor is activated "maintains the sensitivity"of this signaling mech
144
What are the main properties of Heterotrimeric G-Proteins?
- they can be stimulatory or inhibitory
- basic mechanism of GDP/GTP exchange, subunit dissociation, and GTP hydrolysis is the same for all different G-Proteins
- G-proteins are specific to which receptors activate them Gs=activatd by cyclase stimulatory receptors ( Beta adrenergic recptor) Gi=activated by cyclase-inhibitory receptors (ex alpha 2 adrenergic receptors)
- G proteins are also specific for their effectors enzymes (Ex Gs causes the activation of adnylyl cyclase Gt the activation of Cyclic GMP phophodiesterase, Gq cause activation of phospholipase C, Gi causes inhibition of adenyly cyclase)
- G-proteins are universal signal transducers mediating the action of an array of ligands
145
What is the effect of the Cholera Toxin?
the active subunit in the toxin catalyzess the transfer of ADP-ribose from NAD+ to the Gs alpha subunit blocking its GTPase activity and thus resulting in a permanently activated form of G s alpha --> increase in the activitty of its effector enzyme: adenylyl cyclase. this induces massive secretion of water which result in diarrhea
146
what is the effect of the Perussis Toxin?
the inhibitory G proteins are a substrate for it it is prodiuced by the Bordetella pertussis which catalyses ADP-ribozylation of Gi, preventing the displacement of GDP by GTP and blocking the inhibition of adnylyl cyclase. bacteria infects the respiratory tract where its destroys the ciliated epithelial cells that normally sweep away mucus
147
what are the main specificities of Monomeric G-Proteins?
- small G proteins
- 5 major families: Ras, Rho, Rab, Ran and Arf
- -alternate between active and inactive form with GDP/GTP binding
- in GTP bound conformation G protein exposes previously buried regions (Switch 1 and switch 2) that interact with proteins downstream in the signalling pathway
- G -protein inactivates itself by hydrolyzing its bound GTP to GDP
148
where does the GTP ase activity in monomeric G proteins come from?
it is intrinsic and can be increased up to 10^5 by GTP ase activator proteins( GAPS)
these GAPS determin how long the switch will be on
149
in monomeric G proteins what replaces bound GDP to GTP?
this is an intrinsically slow process it is catalysed by guaning nucleotid exchange factors GEFs
150
what is an important monomeric G protein example?
G protein RAS involved in 25 % of all human tumors. these mutants can still bint GAPS but cannot catalyze GTP hydrolysis as a result remain in active state much longer
unregulated stimulation of the RAs signalling pathway which either stimulate cell growth or inhibit apoptosis
151
What triggers CAMP synthesis
it is a secondary messenger triggered by cell surfacer receptors
152
what enzyme catalyzses CAMP synthesis?
it is catalyzed by adenylyl cyclase through removal of ppi from ATP and subsequent formation of cyclci phosphodiester bond betweeen the 3' and 5' postions on the ribose
association of the Gs alpha subunit with the adenyly cyclase turns on the cyclase which catalyzes cAMP synsthesis
short lived, as soon as cAMP is no longer synthesized, consittuively active phosphodiesterases degrade it to 5'-AMP
153
what does CAMP do in the cell?
it activates the specific protein kinase called the cyclic AMP-dependent protein kinse or PKA
154
what is PKA made of? what is its mechanism?
it contains 2 catalytic subunits C and 2 regulatory subunits R
this tetrameric complex is catalytically inactive becasue an autoinhibitory domain of each R subunit occupies the substrate-binding site of each C subunit
binding of the c CAMP to the R subunits results in dissasciation of the R2C2 complex and activation of the C subunits which can phosphoylate diverse substrates within the cell and hence control different intracecullar pathways
155
how does cAMP effect reciprocal control over 2 opposite pathways in the glycogen metabolism?
Synthesis of cAMP results in the phosphorylation and activation of glycogen phosphorylase b, which causes breakdown of glycogen. The same cascade of cAMP and PKA concomitantly causes the phosphorylation and deactivation of hte glycogen synthase
-->end result is that cAMP synthesiezed activates glycogen breakdown and inhibits glycogen synthesis
156
Besides adenylyl cyclase what is the other major signaling system coupled to GPRC's
phospholipace C(PLC)-PLC when activate catalyzes the breakdown of a rare but important plasma membrane phospholibpid the phosphatidylinositol 4,5 bisphosphate (PIP2)
PIP2 is cleaved to insoitol triphosphate IP2 and diacylglycerol DAG
IP3 is a very potent second messenger--> interacts with IP3 receptors on the ER membrane
IP3 R=Ca ++ channel which opens upon Ip3 binding
CA++ relsease from ER=third messenger
Ca++ mediates"lifer or death signals"
157
what kind of receptor is rhdopsin?
it is a GPCR it is very similar to the beta adrenergic receptor
only diff is the Retinal a small vitamin A derived molecule is a permanently bound hormon deep within the cleft formed by the transmembrane domains of rhdopsin
normaly in cis form
when a photon is absorbed it changes to the all trans form=FUNDAMENTAL BASES OF LIGHT DETECTION
Gt is then activated in a manner identical to G protein cycles
158
what are the basic states of the visual transduction pathway?
the alpha subunit of the Gt protrin does not activate either adenylyl cyclase of PLC but instead: cyclic GMP -phosphodiesterase
-->response DECREASES levels of cyclic GMP
159
how does epinephrine mediate receptor desensitization?
prolonged activation of beta adrenergic by high levels of epinephrine results no only in the activation of the G- protein cycle but also in the attachemtn ofthe receptor kinase Beta ARK( Beta- adrenergic receptor kinase)
Beta-ARK phosphorylates serine and threonine residues on the C terminus of the receptor causes another protein Beta- Arrestin to associate
the Arrestin molecule decreases the ability of the Beta- adrenergic receptor to interact with the G-Protein, resulting in desensitization
the receptor -arrestin complex is then internalized by endocytosis
the endocytic vesicle arrestin dissociates; receptor is dephosphorylated and returned to the cell surface
160
what is the mechanism of receptor Guanylyl cyclases?
they are plasma membrane receptor enzymes. when activated they convert GTP to the second messenger guanosine 3'-5' cyclic monophosphate( cyclic GMP,cGM)
many of the actions of cGMP are mediated by cGMP-dependent protin kinase also called protein kinase G
PKG upon acitvation by cGMP phosphorylates Ser nad Thr residues in target proteins
the catalytic and regulator domaines of PKG are in a single polypeptide chaine -part of the regulatory dowmain fits into the substrate binding clet
binding of cGMp forces this pseudosubrstrate out of the binding site opening up the site to garget proteins that contain the PKG consensus site
161
what are 3 examples of receptor Guanylyl Cyclases?
1-GC in the kidney is activated by atrial Natriurectic factor (ANF) which is relseas by cells in the cardiac atrium
2- similar GC in the intestinal epithelial cells is acitvated by guanylin
3- a DISTINCT type of GC is cytosolic GC bound to a heme group that is activated by gas Nitric Oxide( NO)
162
what is the major class of adhesion receptors?
INTEGRINS= dimeric plasma membrane proteins
mediate adhesion of cells to each other and the extracellular matrix
integrins play a cruicial role in proceses that require selective cell-cell interactions like embryonic dev, blood clotting, immune cell function and tumor growth and metastatis
the contain one alph and one beta subunit-each subunit has a short cytoplasmic domain, a single transmembrane helix and a long extracellular ligand-binding domaine
163
where are the receptors for retanoic acid and thryroid found?
they are bond to DNA in the nucleus even in the abscense of ligand
164
where is the receptor for cortisol found?
it is found in the cytosole and enters the nuclesu only after the ligand has bound to it
165
where to nuclear receptors interact with DNA?
they bind toDNA at specific sequences called HREs to enhance gene expression
insome cases ligand binding may inhibit gene transcription ex some trhyroid receptors become transcriptional repressors when hormone binds
166
what are the 2 levels of transcriptional response induced by nuclear receptors?
the ligand binding activates transcription=direct stimulation of a small number of genes -primary response
the protein products of theese genes in turn activate other genes to produce a delayed=secondary response
167
what is the defininf property of lipids?
they are hydrophobic
they are derived from fatty acids
many are amphipathic
168
what role do lipids play?
- the principale form of stored energy
- structural elements of biological memebranes(phospholipids and sterols)
- enzyme cofactors
- intracellular messengers
- light-absorbing pigments
169
what are storage lipids made of and what determines their properities
they are long carboxylic chains, the physical properties of these fatty acids are determined by the number of cis-double bonds
unsaturated=double bonds
170
what determines the melting point of a fatty acid>
the higher the number of unsaturated carbons (double bonds) the lower the melting point -cis double bonds make a kink in the molecule preventing close paking
(chain length has an effect but to a lesser degree)
171
does butter or olive oil have more saturated fatty acids?
butter, harded to break down
172
are staturated or unsaturated fatty acids better energy source?
unsaturated because they can be broken down by the cell very easily- lower melting point and not as tightly packed
easier to break down
173
what are the non polar lipids
triacyglycerols and waxes
174
what are the polar lipids
phoshoglycerides (based on glycerol)
Sphingolipids(based on sphingosine)
sterol (cholesterol)
175
what are the properties of triacylglycerols
non pola lipids
storage lipids
compose of 3 FA each in an ester linkage with a single glycerol
the middle FA is unaturated
very hydrophobic
important for insulation
packed together in large droplets --> fat is mainly stored inthe form of TA has tremendous amount of energy
176
what is the major sotrage form of energy in mamalian cells?
Triacyglycerol- sotre almost twice the energy per grame than glycogen( the major carbohydrate storage form)
177
what is the main class of non polar lipids with pharmaceutical applications?
waxes- non polar lipids with pharmaceutical applications
esters of long saturated and unsatruated FA with long chaine alcohols
generally higher melting points than triacylglycerols
178
what lipids are found in membranes?
polar lipids
phosphoglycerides
sphingolipids
sterols
179
how do phosphoglycerides differ from triacylglycerides?
- polar membran lipids
- 2 fatty acids attached in an ester linkage on the 1st(saturated C16-18) and 2nd carbon(generally unsaturated C18-20) of the glycerol
- highly polar or charged group is attached via a phsophodiester linkage to the 3rd carbon- can be a neg charged, neurtral or positive group "head group"
180
what is the amino acide caryrying phosphoglyceride head group?
phosphatidylserine-only one containing an AA, important in signaling pathways
181
where is cardioliping found?
it is a head group for phosphoglycerides-found in MITHOCONDRIAL membranes
182
what is the basic composition of sphingolipids?
one molecule of the long chain amino alcohol sphingosine , one molecule of SAtruated FA ( C2) and one head group (C1)
they can undergo glycocylation
183
what are the 4 main types of sphingolipids?
1-ceramides (FA +sphingosine)
2- Sphingomyelins( X=phosphorylcholine) Exception have phosphate instead of sugar
3- Glycosphingolipids(X=molecules with one or more sugars mostly OUTER membrane
-cerebrosides(single glucose or galactose
-Globosides (2 or more sugars
4- Gangliosides( at least 3 sugars one must be sialic acid-not line with others)
184
which sphingolipids is also considered a phospholipid?
Sphingomyelins
185
what lipid class play a role in blood type definition
sphingolipids -present in membranes of read blood cell
| addition of a different saccharide as a head group diferentiates blood type
186
what is the cause of tay-sachs?
the lysosomal acucmulation of GM2 ganglioside
| hexoaminidase A non functioning
187
why do lipids cause pathological situations?
lipids have a high turnover rate at themembrane
they undergo constant metabolic turnover -- this is promoted by hydolytic enzyme in lysosomes . each enzyme hydrolyzes a specific bond
when sphingolipid degradation is imparide-- partial breakdown product accumulate incell--> serious disease
188
what are the properties of sterols?
polar membrane lipids
contain a typical steroid nucleus that consists of 4 fused rings
-they are membrane compentents but also PRECURSRS for different products such as hormoned and bile acids
-cholsesterol is major sterol and its synthesis takes place in LIVER
189
how is cholesterol and other lipids carried in the blood plasma?
as lipoprotein particles
these are lipid protein complexes that transport lipids in the blood
have lipids in core and hydrophilic AA chains at the surface - different combination produce particles of different densities
190
what are the 4 types of lipoproteins
1 Chylomicrons(LARGEST, LEAST dense , TA)
2- VLDL(TA, CHOLESTEROL, Cholesteryl Esters)
3-LDL(Cholesterol, cholesteryl esters) bad cholesterol
4- HDL (PROTEIN- rich, LITTLE cholesterol)good cholesterole
191
what are the steps of lipid transport by lipoproteins?
I. Lipids are transported in the bloodstream as lipoproteins. Dietary lipids are transferred as chylomicrons; much of their triglyceride content is released to adipose and muscle tissues during transport through capillaries.
II. Chylomicron remnants, mainly containing apolipoproteins and cholesterol, are taken up by the liver. Endogenous lipids and cholesterol from the liver are delivered to adipose and muscle tissues by VLDL.
III. Removal of lipid from VLDL gradually converts some of it to LDL, which delivers cholesterol to non-hepatic tissues or returns to the liver.
IV. The liver takes up LDL, VLDL and chylomicron remnants by receptor-mediated endocytosis.
Extra cholesterol in non-hepatic tissues is transported back to the liver as HDL, where some of it is converted to bile salts.
192
what is Atherosclerosis?
deposits of fatty substances, cholesterol,cellulare waste products, calcium and other substances that build up in the inner linning of an artery
the build up is called plaque and usually affect large and medium sized arteries
Danger-plaques that rupture cause glood close to form that can block blood flow or travel to another part of the body-it its a blood vessel that feed brain-->STROKE
if supplies arm or legs --can lead to gangrene
