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236 Cards in this Set
- Front
- Back
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Where do the following processes take place
-Fatty acid oxidation (beta-oxidation) -acetyl CoA production -TCA cycle -oxidative phosphorylation |
mitochondria
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where do the following processes take place
-glycolysis -FA synthesis -HMP shunt -Protein synth (RER) -Steroid synth (SER) |
cytoplasm
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Where do these processes occur
-heme synthesis -urea cycle -gluconeogenesis |
Both mitochondria and cytoplasm
HUGs take 2 |
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Enzyme descriptors
Enzyme that uses ATP to add high energy phosphate group to substrate |
kinase
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Enzyme descriptors
Enzyme that adds inorganic phosphate onto substrate without using ATP |
phosphorylase
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Enzyme descriptors
Enzyme that removes phosphate group from substrate |
phosphatase
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Enzyme descriptors
Enzyme that oxidizes substrate |
dehydrogenase
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Enzyme descriptors
Enzyme that adds 1 carbon with the help of biotin |
carboxylase
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Rate limiting steps
Glycolysis |
Phosphofructokinase-1
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Rate limiting steps
Gluconeogenesis |
Fructose 1,6-bisphosphatase
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Rate limiting steps
TCA cycle |
isocitrate dehydrogenase
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Rate limiting steps
Glycogen synthesis |
Glycogen synthase
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Rate limiting steps
Glycogenolysis |
glycogen phosphorylase
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Rate limiting steps
HMP shunt |
Glucose 6 phosphate dehydrogenase
G6PD |
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Rate limiting steps
De novo pyrimidine synthesis |
Carbamoyl phosphate synthetase II
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Rate limiting steps
De novo purine synthesis |
Glutamine PRPP aminotransferase
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Rate limiting steps
Urea cycle |
Carbamoyl phosphate synthetase I
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Rate limiting steps
Fatty acid synthesis |
Acetyl CoA Carboxylase
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Rate limiting steps
Fatty acid oxidation |
Carnitine acyltransferase I
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Rate limiting steps
Ketogenesis |
HMG CoA synthase
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Rate limiting steps
Cholesterol synthesis |
HMG CoA reductase
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Glycolysis/ATP production
How many ATP does each yield and where does each occur a. malate-aspartate shuttle b. glycerol-3-phosphate shuttle |
a. 32, heart and liver
b. 30, muscle |
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Glycolysis/ATP production
Anaerobic glycolysis - how much ATP/glucose? |
2 ATP/glucose
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General use of ATP
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couple ATP hydrolysis to energetically unfavorable reactions
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Activated carriers in metabolism
Phosphoryl groups |
ATP
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Activated carriers in metabolism
Electrons |
NADH, NADPH, FADH2
(vitamin B3 niacin) |
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Activated carriers in metabolism
Acyl groups What is the function of this? |
Coenzyme A, lipoamide
Provides C atoms to TCA cycle, oxidized for energy |
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Activated carriers in metabolism
1 carbon units |
tetrahydrofolates
(Folic acid) |
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Activated carriers in metabolism
CO2 |
biotin
(Vitamin B7) |
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Activated carriers in metabolism
CH3 groups depends on what vitamins |
SAM
(vitamins B12, folate) |
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Activated carriers in metabolism
Aldehydes |
TPP
(Vitamin B1 thiamine) |
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Universal Electron acceptors
3 molecules |
NAD, NADP, FAD
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Universal Electron acceptors
NADPH a. product of which pathway b. used in what types of processes |
a. HMP shunt
b. anabolic - steroid and FA synth, supplies electrons |
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Universal Electron acceptors
NAD what types of processes is it used in |
Catabolic processes, carries electrons away as NADH
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Universal Electron acceptors
All of these processes use what electron acceptor -anabolic processes -respiratory burst (release of ROS) -P450 (oxidizes organic substances) -glutathione reductase (reduces glutathione disulfide to sulfhydryl, an antioxidant) |
NADPH
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Hexokinase vs. Glucokinase
General function |
phosphorylates glucose --> G6P
first step of glycolysis, glycogen synthesis in liver |
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Hexokinase vs. Glucokinase
where does each act |
hexokinase = ubiquitous
glucokinase = -liver--> phophorylates glucose to allow it to be sequestered in liver after a meal --> liver serves as blood glucose 'buffer' -b-cells of pancreas --> control insulin release |
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Hexokinase vs. Glucokinase
how do the Km and Vm compare on each |
Hexokinase = low Km (high affinity), low Vm (low capacity)
glucokinase = high Km (low affinity), high Vm (high capacity) GLUcokinase is a GLUtton because it cannot get enough (high Vm) |
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Hexokinase vs. Glucokinase
Responses to insulin |
Hexokinase = Not induced by insulin
Glucokinase = induced by insulin |
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Hexokinase vs. Glucokinase
Feedback |
Hexokinase = inhibited by G6P
Glucokinase = No direct feedback inhibition |
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Glycolysis
2 rxns that use ATP |
1. Glucose --> G6P (HK/GK)
2. F6P --> F-1,6-BP (PFK-1) |
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Glycolysis
Glucose --> G6P (HK/GK) Pos/neg feedback? |
G6P --> negative feedback
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Glycolysis
F6P --> F-1,6-BP (PFK-1) Pos/neg feedback |
Positive feedback: AMP, F-2,6-BP
Negative feedback: ATP, citrate |
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Glycolysis
2 reactions that produce ATP |
1. 1,3-BPG --> 3-PG (phosphoglycerate kinase)
2. PEP --> Pyruvate (pyruvate kinase) |
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Glycolysis
1 reaction that produces NADH |
G3P --> 1,3 BPG
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Glycolysis
3 irreversible reactions |
1. Glucose --> G6P (HK/GK)
2. F6P --> F-1,6-BP (PFK-1) 3. PEP --> Pyruvate (pyruvate kinase) |
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Glycolysis
PEP --> Pyruvate (pyruvate kinase) Pos/neg feedback |
Positive: F-1,6-BP
Negative: ATP, alanine |
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Glycolysis
Pyruvate --> acetyl CoA (pyruvate dehydrogenase) Pos/Neg feedback |
Negative: ATP, NADH, Acetyl-CoA
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Glycolysis
Fructose-2,6-BP a. in what stage is it made b. what does it do |
a. made in fed state
F6P --> F-2,6-BP (PFK-2) b. strong allosteric activator of PFK-1, increases glycolysis by increasing this rxn F6P --> F-1,6-BP (PFK-1) |
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Glycolysis: Fructose-2,6-BP
a. mechanism by which it is affected by the fasting state b. mechanism by which it is affected in the fed state |
a. high glucagon --> high cAMP --> high PKA --> high FBPase-2, low PFK-2 (low production of F-2,6-BP)
b. High insulin --> low cAMP --> low PKA --> low FBPase-2, high PFK-2 (high F-2,6-BP) --> activator of PFK-1 and glycolysis |
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Pyruvate dehydrogenase complex
What is the written out reaction this complex catalyzes |
Pyruvate + NAD + CoA --> Acetyl-CoA + CO2 + NADH
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Pyruvate dehydrogenase complex
5 cofactors required |
1. TPP - vitamin B1 (thiamine)
2. FAD - B2, riboflavin 3. NAD - B3, niacin 4. CoA - B5, pantothenate 5. Lipioc acid |
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Pyruvate dehydrogenase complex
When is this complex activated? When is activity decreaed? |
Exercise!
Increase NAD/NADH ratio, ADP, and Ca --> increased activity of complex Decreased if you have an increase in NADH, ATP, or acetyl-CoA |
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Pyruvate dehydrogenase complex
Similar to what other complex (TCA cycle), and what rxn does this complex catalyze |
a-ketoglutarate dehydrogenase complex
a-ketoglutarate --> succinyl-CoA |
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Patient has
-vomiting -rice water stools -garlic breath dx? mechanism |
arsenic poisoning
inhibits lipoic acid, so pyruvate dehydrogenase complex cannot work |
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Pyruvate dehydrogenase deficiency
a. causes? b. what molecules build up c. findings |
a. congenital or acquired (alcoholics have B1 deficiency)
b. pyruvate and alanine --> lactic acidosis c. neurological defecits |
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Patient is an alcoholic who has neurological defecits secondary to B1 deficiency
What is happening? How can you treat? |
B1 deficiency --> pyruvate dehydrogenase deficiency
give ketogenic nutrients (high fat, high Leucine, high Lysine) ketone bodies --> acetyl CoA --> Fatty acids for energy |
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Pyruvate metabolism
4 possible pathways for pyruvate |
1. Converted to alanine by ALT in muscle --> carries amino groups from muscle to liver
2. Converted to oxaloacetate (Pyruvate carboxylase) --> replenish TCA or used in gluconeogenesis 3. converted to acetyl-CoA --> glycolysis 4. Converted to lactate --> anaerobic glycolysis |
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Pyruvate metabolism
What happens to pyruvate in muscle and why? |
ALT adds amino groups (from amino acid breakdown) to pyruvate to make alanine --> carried to liver --> converted back to pyruvate --> gluconeogenesis --> glucose delivered back to muscle
Allows muscle to have glucose without having to do the work of gluconeogenesis of pyruvate |
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Pyruvate metabolism
What happens to pyruvate in normal glycolytic pathway? What is produced? |
Pyruvate --> acetyl CoA (Pyruvate dehydrogenase), irreversible
produces NADH, CO2 |
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Pyruvate metabolism
What happens to pyruvate in RBCs, WBCs, kidney medulla, lens, testes, and cornea why? |
Pyruvate --> lactate (lactate dehydrogenase, consumes NADH)
These tissues use anaerobic glycolysis |
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TCA cycle
order of intermediates from acetyl-CoA to oxaloacetate |
"Citrate Is Krebs Starting Substrate For Making Oxaloacetate"
Citrate Isocitrate a-Ketoglutarate Succinyl-CoA Succinate Fumarate Malate Oxaloacetate |
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TCA cycle
Produced in the rxn pyruvate--> acetyl-CoA |
1 NADH, 1 CO2
runs 2x per glucose |
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TCA cycle
3 irreversible enzymes |
1. citrate synthase
2. isocitrate dehyrdogenase 3. a-ketoglutarate dehydrogenase |
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TCA cycle
a. Net production per acetyl CoA b. How much ATP is this c. How much per glucose |
a. 3 NADH, 1 FADH2, 1 GTP
b. 12 ATP/acetyl CoA c. everything 2x |
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TCA cycle
3 rxns producing NADH |
1. Isocitrate --> a-ketoglutarate (isocitrate DH)
2. a-ketoglutarate --> succinyl-CoA (a-ketoglutarate DH) 3. Malate --> oxaloacetate |
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TCA cycle
1 rxn producing FADH2 |
Succinate --> fumarate
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TCA cycle
1 rxn producing GTP |
Succinyl-CoA --> succinate
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TCA cycle
Isocitrate dehydrogenase a. rxn b. pos. feedback c. neg. feedback |
a. isocitrate --> a-ketoglutarate
b. ADP c. ATP, NADH |
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TCA cycle
What co-factors does a-ketoglutarate DH need? Similar to what? |
similar to pyruvate dehydrogenase
needs B1, B2, B3, B5, lipoic acid |
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ETC
how do NADH electrons from glycolysis/TCA enter mitochondria (2 ways) |
1. malate-aspartate
2. glycerol-3-phosphate shuttle |
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ETC
a. Where do NADH electrons go once they enter mitochondria b. where do FADH2 electrons go |
a. complex I
b. complex II (succinate dehydrogenase) - lower energy level |
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ETC
What shuttles electrons from complex I/II to complex III what shuttles electrons from complex III to complex IV |
1. CoQ
2. Cytochrome C |
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ETC
What happens as electrons are shuttled from complex to complex |
Formation of H gradient, which drives mitochondrial ATPase to form ATP in the mitochondrial matrix
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ETC
How much ATP per NADH? per FADH2? |
NADH --> 3 ATP
FADH2 --> 2 ATP |
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ETC
4 poisons that act by inhibiting electron transport directly --> decrease H gradient --> block ATP synthesis |
Roteonone
CN- Antimycin A CO |
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ETC
One oxidative phosphorylation poison that works by directly inhibiting mitochondrial ATPase --> increased H gradient but no ATP production |
oligomycin
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ETC
Poisons that work by increasing permeability of mitochondrial membrane --> decrease H gradient but electron transport continues --> No ATP production, high O2 consumption, heat produced |
Aspirin (accounts for fever after aspirin overdose)
2,4-Dinitrophenol thermogenin in brown fat |
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Gluconeogenesis
4 irreversible enzymatic steps |
1. pyruvate --> oxaloacetate (pyruvate carboxylase)
2. Oxaloacetate --> PEP (PEP carboxykinase) 3. F-1,6-BP --> F6P (Fructose-1,6-BPase) 4. G6P --> glucose (G6Pase) Enzymes: "Pathway Produces Fresh Glucose" |
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Gluconeogenesis
pyruvate carboxylase a. rxn b. where c. what does it require d. pos/neg feedback |
a. pyruvate --> oxaloacetate
b. mitochondria c. biotin, ATP d. pos: acetyl-CoA |
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Gluconeogenesis
PEP carboxykinase a. rxn b. where c. what does it require |
a. oxaloacetate --> PEP
b. cytosol c. GTP |
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Gluconeogenesis
F-1,6-BPase a. rxn b. where |
a. F-1,6-BP --> F6P
b. cytosol |
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Gluconeogenesis
G6Pase a. rxn b. where |
a. G6P --> glucose
b. ER |
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Gluconeogenesis
3 places where it occurs |
mostly in liver, also in kidney and intestinal epithelium
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What happens if you are missing gluconeogenic enzymes?
Can muscle undergo gluconeogenesis? why/why not? |
Hypoglycemia
No, lacking G6Pase |
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Gluconeogenesis
Odd chain vs. even chain fatty acids |
odd chain --> 1 molecule of propionyl CoA --> succinly-CoA (requires biotin) --> oxaloacetate (via TCA) --> gluconeogenesis
Even chains cannot participate in gluconeogenesis because they yeild only acetyl CoA equivalents |
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HMP shunt
Purpose? |
Provide NADPH from G6P (if abundantly available)
NADPH used for anabolic, reductive rxns (ex: glutathione reduction to make antioxidant) |
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HMP shunt
a. where b. what is produced c. what is NOT produced |
a. cytoplasm in lactating mammary glands, liver, adrenal cortex (sites of FA or steroid synth), RBCs
b. NADPH, ribose (nucleotide synthesis), glycolytic intermediates (G3P, F6P) c. NO ATP |
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HMP shunt
2 phases (reactions, enzymes, and cofactors) |
1. oxidative, reversible
G6P --> 2NADPH, CO2, Ribulose-5-P (G6P dehydrogenase, rate limiting) 2. non-oxidative, irreversible Ribulose-5-P --> Ribose-5-P, G3P, F6P (transketolases, B1) |
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Disorders of Galactose metabolism
2 steps to galactose metabolism |
1. Galactose --> galactose-1-P (galactokinase, ATP)
2. galactose-1-P --> glucose-1-P (galactose-1-P uridyltransferase, UDP-glucose) |
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Patient is an infant that has
-galactose in blood and urine -infant cataracts -failure to track objects or develop a social smile dx? What is happening? genetics? |
galactokinase deficiency
buildup of galactitol (reduced galactose) autosomal recessive |
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Patient is an infant experiencing
-failure to thrive -jaundice -hepatomegaly -infantile cataracts -mental retardation dx? genetics? what is happening? How do you treat? |
classic galactosemia - aut. recessive
absence of galactose-1-P uridyltransferase --> buildup of toxic substances (ex: galactitol in lens) Treat: exclude galactose and lactose (glucose + galactose) from diet |
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Sorbitol
Where does it come from What is it metabolized to |
glucose --> sorbitol (aldose reductase, NADPH)
sorbitol --> fructose (sorbitol dehydrogenase, NAD) |
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Sorbitol
Which tissues express ONLY aldose reductase? What are these tissues at risk for? |
Schwann cells, lens, retina, kidney
at risk for accumulating intracellular sorbitol --> cataracts, retinopathy, peripheral neuropathy |
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Sorbitol
Which tissues express both aldose reductase and sorbitol dehydrogenase |
liver, ovaries, seminal vesicles
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Patient is a diabetic with chronic hyperglycemia. Now experiences
-cataracts -retinopathy -peripheral neuropathy what is happening? |
glucose being converted to sorbitol in lens, retina, schwann cells, and kidneys, but not further metabolized to fructose (b/c these lack sorbitolDH)
accum. sorbitol --> osmotic damage |
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Patient ingests dairy, now has
-bloating, cramps -osmotic diarrhea dx? cause? treat? |
lactase deficiency
loss of brush border enzyme due to age, genetics (AA, Asians), or following gastroenteritis avoid dairy or give lactase pills |
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Amino acids
what form of amino acids is found in proteins |
L-form
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Essential amino acids that are glucogenic (4)
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Met
Val Arg His |
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Essential amino acids that are both glucogenic and ketogenic
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Ile
Phe Thr Trp |
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Essential amino acids that are ketogenic
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Leu
Lys |
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Acidic amino acids
What is their charge at body pH |
Asp
Glu neg. charge at body pH |
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Basic amino acids
which is the most basic Which has no charge at body pH |
Arg
Lys His Arg is most basic His has no charge at body pH |
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2 amino acids required during growth periods
2 amino acids found in histones (which bind neg. charged DNA) |
Arg, His
Arg, Lys |
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Amino acid catabolism
2 products and what happens to them |
1. Common metabolites (pyruvate, acetyl-CoA) --> metabolic fuel
2. NH4 --> converted to urea, excreted in kidneys |
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Urea
3 components where do they come from |
First NH2 --> from NH4
carboxylic acid group --> from CO2 Second NH2 from aspartate |
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Rate limiting step in urea cycle
Where does it take place |
NH4 + CO2 --> carbamoyl phosphate (carbamoyl phosphate synthetase I, 2ATP)
Liver Mitochondria |
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2 places where the urea cycle takes place
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liver mitochondria (just rate limiting step)
liver cytoplasm (the rest of the rxn) |
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Urea cycle
Order of intermediates |
Ordinarily Careless Crappers Are Also Frivolous About Urination
Ornithine +Carbamoyl phosphate --> Citrulline + Aspartate --> Arginosuccinate --> Fumarate + Arginine --> Urea |
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Transport of ammonium by alanine and glutamate
What happens in muscle |
NH3 from amino acids tranferred to a-ketoglutarate --> glutamate
NH3 on glutamate transferred to pyruvate --> alanine Alanine to liver |
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Transport of ammonium by alanine and glutamate
What happens in liver |
alanine gives NH3 back to a-ketoglutarate to make glutamate, which is then converted to urea
Alanine becomes pyruvate --> glucose --> transferred back to muscle --> back to pyruvate |
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Hyperammonemia
2 ways of getting it |
1. acquired - liver disease
2. genetic - urea cycle deficiencies |
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Patient comes in with
-tremor -slurring of speech -somnolence -vomiting -cerebral edema -blurred vision dx? What is happening? what process is being hindered and how? |
ammonia intoxication
NH4 builds up, depletes a-ketoglutarate --> inhibits TCA cycle |
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3 treatments for hyperammonemia
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1. limit protein in diet
2. benzoate 3. phenylbutyrate these bind to amino acids, lead to excretion |
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In first few days of life, baby presents with
-orotic acid in urine and blood -decreased BUN -tremor, somnolence, vomiting, cerebral edema symptoms suggest what is going on? dx? genetics? |
Urea cycle disorder:
-ammonia is building up (symptoms of hyperammonemia) -orotic acid building up (excess carbamoyl phosphate converted to orotic acid) -not making urea Ornithine transcarbamoylase deficiency (cannot turn carbamoyl phosphate + ornithine --> citrulline) x-linked recessive |
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How is the genetic inheritance of OTC (ornithine transcarbamoylase) deficiency different from other urea cycle deficiencies
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OTC - x linked recessive
others - autosomal recessive |
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Phenylalanine
What can it make? |
Phe --> Tyrosine (can make thyroxine) --> Dopa (can make melanin) --> Dopamine --> NE --> Epi
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2 things that derive from tryptophan
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1. Trp + B6 --> niacin --> NAD/NADP
2. Trp + BH4 --> serotonin --> melatonin |
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AA derivatives
One thing that derives from histidine |
Histidine + B6 --> histamine
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Transport of ammonium by alanine and glutamate
What happens in muscle |
NH3 from amino acids tranferred to a-ketoglutarate --> glutamate
NH3 on glutamate transferred to pyruvate --> alanine Alanine to liver |
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Transport of ammonium by alanine and glutamate
What happens in liver |
alanine gives NH3 back to a-ketoglutarate to make glutamate, which is then converted to urea
Alanine becomes pyruvate --> glucose --> transferred back to muscle --> back to pyruvate |
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Hyperammonemia
2 ways of getting it |
1. acquired - liver disease
2. genetic - urea cycle deficiencies |
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Patient comes in with
-tremor -slurring of speech -somnolence -vomiting -cerebral edema -blurred vision dx? What is happening? |
ammonia intoxication
NH4 builds up, depletes a-ketoglutarate --> inhibits TCA cycle |
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3 treatments for hyperammonemia
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1. limit protein in diet
2. benzoate 3. phenylbutyrate these bind to amino acids, lead to excretion |
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In first few days of life, baby presents with
-orotic acid in urine and blood -decreased BUN -tremor, somnolence, vomiting, cerebral edema symptoms suggest what is going on? dx? genetics? |
Urea cycle disorder:
-ammonia is building up (symptoms of hyperammonemia) -orotic acid building up (excess carbamoyl phosphate converted to orotic acid) -not making urea Ornithine transcarbamoylase deficiency (cannot turn carbamoyl phosphate + ornithine --> citrulline) x-linked recessive |
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How is the genetic inheritance of OTC (ornithine transcarbamoylase) deficiency different from other urea cycle deficiencies
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OTC - x linked recessive
others - autosomal recessive |
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Phenylalanine
What can it make? |
Phe --> Tyrosine (can make thyroxine) --> Dopa (can make melanin) --> Dopamine --> NE --> Epi
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2 things that derive from tryptophan
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1. Trp + B6 --> niacin --> NAD/NADP
2. Trp + BH4 --> serotonin --> melatonin |
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AA derivatives
One thing that derives from histidine |
Histidine + B6 --> histamine
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Transport of ammonium by alanine and glutamate
What happens in muscle |
NH3 from amino acids tranferred to a-ketoglutarate --> glutamate
NH3 on glutamate transferred to pyruvate --> alanine Alanine to liver |
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Transport of ammonium by alanine and glutamate
What happens in liver |
alanine gives NH3 back to a-ketoglutarate to make glutamate, which is then converted to urea
Alanine becomes pyruvate --> glucose --> transferred back to muscle --> back to pyruvate |
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Hyperammonemia
2 ways of getting it |
1. acquired - liver disease
2. genetic - urea cycle deficiencies |
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Patient comes in with
-tremor -slurring of speech -somnolence -vomiting -cerebral edema -blurred vision dx? What is happening? |
ammonia intoxication
NH4 builds up, depletes a-ketoglutarate --> inhibits TCA cycle |
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3 treatments for hyperammonemia
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1. limit protein in diet
2. benzoate 3. phenylbutyrate these bind to amino acids, lead to excretion |
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In first few days of life, baby presents with
-orotic acid in urine and blood -decreased BUN -tremor, somnolence, vomiting, cerebral edema symptoms suggest what is going on? dx? genetics? |
Urea cycle disorder:
-ammonia is building up (symptoms of hyperammonemia) -orotic acid building up (excess carbamoyl phosphate converted to orotic acid) -not making urea Ornithine transcarbamoylase deficiency (cannot turn carbamoyl phosphate + ornithine --> citrulline) x-linked recessive |
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How is the genetic inheritance of OTC (ornithine transcarbamoylase) deficiency different from other urea cycle deficiencies
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OTC - x linked recessive
others - autosomal recessive |
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Phenylalanine
What can it make? |
Phe --> Tyrosine (can make thyroxine) --> Dopa (can make melanin) --> Dopamine --> NE --> Epi
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2 things that derive from tryptophan
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1. Trp + B6 --> niacin --> NAD/NADP
2. Trp + BH4 --> serotonin --> melatonin |
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AA derivatives
One thing that derives from histidine |
Histidine + B6 --> histamine
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AA derivatives
porphyrin, heme derived from which AA |
Glycine (+B6)
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AA derivates
Creatine, urea, NO derived from which AA |
Arg
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AA derivatives
2 things derived from glutamate |
1. Glu + B6 --> GABA
2. Glu --> Glutathione |
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Catecholamine synth
5 enzymes, what do they catalyze and what cofactors do they use (Phe --> Epi pathway) |
1. Phe hydroxylase (Phe --> Tyr)
-THB 2. Tyr hydroxylase (Tyr --> Dopa) -THB 3. Dope decarboxylase (Dopa --> dopamine) -uses B6 4. Dopamine b-hydroxylase (dopamine --> NE) -uses vitamin c 5. PNMT (NE --> Epi) -uses SAM |
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Which step in catecholamine synthesis is inhibited by carbidopa
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Dopa decarboxylase
Dopa --> dopamine (vit. B6) |
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Breakdown products via MAO and COMT
a. Dopamine b. NE c. Epi |
a. homovanillic acid (HVA)
b. Vanillylmandelic acid (VMA) c. Metanepherine |
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baby has
-mental retardation -growth retardation -seizures -fair skin -eczema dx? 2 possible causes? -musty, mousy odor |
PKU
decrease in Phe hydroxylase or THB --> buildup of Phe, loss of Tyr |
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2-3 days after birth, you screen a baby and find they have a loss of Phe hydroxylase
a. what condition? b. genetics? incidence? c. how do you treat |
a. PKU
b. aut. recessive, 1:10,000 c. decrease Phe, increase Tyr in diet |
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Baby with musty odor is found to have increase in phenylketones in urine (phenylacetate, pheyllactate, phenylpyruvate)
what are 2 possible causes? |
PKU
decrease in Phe hydroxylase or in THB cofactor |
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Infant has microcephaly, mental retardation, growth retardation, congenital heart defects
What is going on |
Maternal PKU
mom had poor dietary control during pregnancy, buildup of Phe hurt baby |
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Respiratory burst
what is activated first? What process is the burst important for? |
activation of membrane bound NADPH oxidase (in PMNs, macrophages)
important in immune response --> rapid release of ROI |
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Respiratory burst
what is the role of the following? a. NADPH oxidase b. superoxide dismutase c. myeloperoxidase where do all three act |
all act in the phagosome
a. NADPH gives an electron to oxygen, creating an oxygen free radical b. O2 free radical --> H2O2 c. catalyzes H202 + Cl --> HOCl (bleach, hypochlorite) --> kills bacteria |
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Respiratory burst
what do the following do a. glutathione peroxidase b. glutathione reductase c. G6P dehydrogenase (G6PD) where do all three act |
Act in neutrophil
a. GSH (reduced form) donates electrons to H202 --> H20 b. NADPH donates electrons to GSSG to regenerate reduced glutathione (GSG) c. G6P converted to 6PG, yielding NADPH (first step of HMP shunt) |
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Respiratory burst
What is chronic granulomatous disease? What types of infections are these people susceptible to and why? |
NADPH oxidase deficiency --> cannot make own ROIs (and thus cannot make H202 or HOCl)
Normally, WBCs can use H202 generated by the invading organism to convert to ROIs But if catalase positive (S. aureus, aspergillus), they neutralize their own H202 --> WBCs cannot generate ROIs |
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what is the most common human enzyme deficiency?
genetics? race association? |
G6PD deficiency --> cannot produce NADPH --> cannot detoxify free radicals and peroxides
x-linked recessive higher in blacks |
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Patient has hemolytic anemia secondary to G6PD deficiency
Pathogenesis? 2 inciting causes? |
No G6PD --> no NADPH in RBCs --> cannot reduct GSSH to GSH --> cannot neutralize free radicals and peroxides
1. oxidizing agents (fava beans, sulfonamides, primaquine, antiTB drugs) 2. infection (free radicals generated during inflammatory response diffuse into RBCs) |
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G6PD deficiency
a. what are Heinz bodies b. what are bite cells c. what condition do these indicate |
a. Heinz = oxidized Hemoglobin precipitated within RBCs
b. Bite = phagocytic removal of Heinz bodies by macrophages c. indicate hemolytic anemia |
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Patient has fructose in the blood, but no other symptoms
a. where is the defect b. genetics c. why are there no symptoms |
a. defect in fructokinase
b. autosomal recessive c. benign because fructose does not enter cells |
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Patient has buildup of Fructose-1-Phosphate -->
-hypoglycemia -jaundice -cirrhosis -vomiting pathophysiology? treatment? |
hereditary deficiency of aldolase B --> fructose intolerance
Buildup of Fructose-1-P decreases available phosphate --> inhibits glycogenolysis and gluconeogenesis Treat with decreased fructose and sucrose (fructose + glucose) in diet |
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Fructose metabolism - where?
what rxns are catalyzed by these enzymes a. fructokinase b. aldolase B c. triose kinase |
Liver
a. Fructose --> F-1-P (ATP) b. F-1-P --> DHAP and Glyceraldehyde (bypasses rate limiting step of glycolysis by doing this) c. glyceraldehyde --> G3P (DHAP also converts to G3P) --> glycolysis |
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Genetics of fructose intolerance
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autosomal recessive deficiency in aldolase B
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Patient comes in with
-debilitating arthralgias -dark CT, dark sclera, dark urine lots of homogentisic acid in urine a. dx? b. genetics? c. Pathophys? d. course? |
a. alkaptonuria (onchronosis)
b. aut. recessive c. defect in degradation of tyrosine to fumarate; buildup of homogentisic acid (alkapton), which can be toxic to cartilage d. benign |
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Albinism
2 possible causes |
1. tyrosinase (inability to convert tyrosine to melanin) - aut. recessive
2. Defective tyrosine transporters (not enough tyrosine around the make melanin) -possibly due to lack of migration of neural crest cells |
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Albinism
a. complications b. genetics, how is it different from ocular albinism |
a. increases risk of skin cancer (no melanin)
b. locus heterogeneity, variable inheritance ocular albinism is x-linked recessive |
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Patient presents with
-tons of homcysteine in urine -mental retardation -osteoperosis -tall stature -kyphosis (hunchback) -lens subluxation (down and in) -atherosclerosis dx? pathophys? what becomes essential to supplement? |
homocystinuria
defect in methionine metabolism, cysteine becomes essential |
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Patient has homocysteinuria
what are 3 possible causes and how do you treat? |
1. cystathione synthase deficiency
-give dietary Cys, B12, and folate; decrease Met 2. decreased affinity of cystathione synthase for B6 -give lots of B6 in diet 3. Homocystein methyltransferase deficiency -give Cys, take out Met from diet |
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Patient has
-tons of cystine in urine -cystine staghorn caliculi (kidney stones) what's wrong |
cystinuria = autosomal recessive defect in renal amino acid transporter of cysteine, ornithine, lysine, and arginine in PCT of kidneys
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cystinuria
a. what is cystine? b. genetics? c. incidence? d. Treatment? |
a. cystine = 2 cysteines connected by disulfide bond
b. aut. recessive c. 1: 7000 common d. give acetazolamide to alkalinize urine |
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Patient has
-mental retardation -CNS defects -urine smells like maple syrup dx. path? |
maple syrup urine disease
decreased a-ketoacid dehydrogenase --> buildup of branched chain amino acids (Ile, Leu, Val) "I Love Vermone Maple Syrup (with branches)" |
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Patient presents with
-lots of tryptophan in urine -dermatitis, dementia, diarrhea what do these symptoms indicate? genetics? |
Hartnup disease
-Trp in urine high due to defective neurtral amino acid transporter on renal and intestinal epithelial cells -Pellagra symptoms due to loss of niacin (due to loss of Trp) aut. recessive |
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Glycogen regulation
3 substances that activate glycogenolysis |
1. Glucagon (liver)
2. Epinepherine (liver, muscle) 3. Ca/Calmodulin in muscle |
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Glycogen regulation
mechanism by which glucagon and epinepherine activate glycogenolysis |
glucagon and epi --> activate Adenylyl cyclase --> cAMP --> activate PKA --> activate glycogen phosphorylase kinase --> activates glycogen phosphorylase
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Glycogen regulation
Mechanism by which muscle Ca/calmodullin activates glycogenolysis |
activates glycogen phosphorylase kinase directly --> activates --> activates glycogen phosphorylase --> activates glycogenolysis
muscle activity is coordinated with glycogenolysis |
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Glycogen regulation
mechanism by which insulin decreases glycogenolysis |
Insulin --> dimerization of receptor tyrosine kinase --> activates protein phosphatase --> removes P (inactivates) from both glycogen phosphorylase kinase and glycogen phosphorylase
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Glycogen
types of bonds a. branches b. linkages |
a. a(1,6) bonds
b. a(1,4) bonds |
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glycogen
function in a. skeletal muscle b. hepatocytes |
a. glycogen undergoes glycogenolysis --> glucose --> rapidly metabolized by glycolysis in exercise (no G6Pase to make glucose)
b. glycogen stored, glycogenolysis to maintain blood sugar |
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glycogen synthesis/olysis
what rxns do the following enzymes catalyze a. UDP-glucose pyrophosphorylase b. glycogen synthase c. branching enzyme d. glycogen phosphorylase e. debranching enzyme |
a. G1P + UTP --> UDP-glucose
b. adds monomers of UDP-glucose in a(1,4) linkages --> chain c. removes 6-7 residues on ends and puts them in an a(1,6) link, only on a chain at least 11 residues long d. cleaves a(1,4) bonds from ends of chain --> G1P monomers e. rearranges chain by removing a(1,6) linkages and putting residues in chain |
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Besides the normal glycogenolysis pathway in liver, where else is glycogen broken down (minor)
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small amount degraded in lysosomes by a(1,4) glucosidase
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What is dextran?
What is its limit? |
straight chain of a(1,6) linked glucose with a(1,3) branches
limit 4 glucose residues |
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4 steps of glycogenolysis
1. glycogen phosphorylase 2. debranching enzyme 3. phosphoglucomutase 4. G6Pase |
1. glycogen phosphorylase cleaves a(1,4) links on a branch (releasing G1P residues) until 4 residues left
2. Debranching enzyme removes 3 residues from branch, add them to chain (1,4) Also cleaves the a(1,6) residue of the branch (yields glucose) 3. G1P --> G6P 4. G6P --> glucose |
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Glycogen storage diseases
a. how many types b. all result in what c. what are 4 |
a. 12 types
b. all result in accumulation of glycogen within a cell c. Very Poor Carbohydrate Metabolism -Von Gierke's -Pompe's -Cori's -McArdle's |
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Patient presents with
-severe fasting hypoglycemia -HIGH glycogen in liver -high blood lactate -hepatomegaly dx? Enzyme deficiency |
Von Gierke's (type I glycogen storage disease)
Deficient G6P --> accumulation of glycogen in liver, decreased glycogenolysis and gluconeogenesis -G6P inhibits lactic acid conversion to pyruvate, so it builds up |
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patient presents with
-high glycogen in liver -cardiomegaly -early death dx? enzyme? |
Pompe's (type II glycogen storage disease)
"Pompe's trashes the Pump (heart, liver, muscle) lysosomal a-1,4-glucosidase (acid maltase) deficiency --> no lysosomal degradation of glycogen |
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patient presents with
-fasting hypoglycemia -glycogen buildup in liver -hepatomegaly -normal lactate levels dx. enzyme? why is this a milder condition? |
Cori (type III glycogen storage disease)
debranching enzyme (a-1,6-glucosidase) milder because you can still do gluconeogenesis |
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patient presents with
-lots of glycogen in muscle -painful muscle cramps -myoglobinuria with strenuous exercise dx. enzyme. |
McArdle's (Muscle)
Type V glycogen storage disease glycogen phosphorylase in skeletal muscle |
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Lysosomal storage diseases
patient presents with -peripheral neuropathy of hands/feet -angiokeratomas (cutaneous capillary lesions --> red/blue marks) -CV, renal disease dx? a. deficient enzyme b. accumulated substrate c. inheritance |
Fabry's disease
a. a-galactosidase A b. ceramide trihexoside c. XR |
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Lysosomal storage diseases
a. deficient enzyme b. accumulated substrate c. inheritance patient presents with -heptaosplenomegaly -aseptic necrosis of femur -bone crises -macrophages that look like crumpled tissue paper |
Gaucher's disease (most common)
a. b-glucocerebrosidase b. glucocerebroside c. AR |
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Lysosomal storage diseases
a. deficient enzyme b. accumulated substrate c. inheritance patient presents with -progressive neurodegeneration -hepatosplenomegaly -cherry-red spot on macula -foam cells |
Niemann-Pick
a. sphingomyelinase b. sphingomyelin c. AR "No man picks (niemann pick) his nose with his Sphinger (sphingomyelinase)" |
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Lysosomal storage diseases
a. deficient enzyme b. accumulated substrate c. inheritance patient presents with -progressive neurodegeneration -developmental delay -cherry red spot on macula -lysosomes with onion skin -NO hepatosplenomegaly |
Tay Sachs
a. hexosaminidase A b. GM2 ganglioside c. AR "tay-saX lacks heXoaminidase" |
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Lysosomal storage diseases
a. deficient enzyme b. accumulated substrate c. inheritance patient presents with -peripheral neuropathy -developmental delay -optic atrophy -globoid cells |
Krabbe disease
a. Galactocerebrosidase b. galactocerebroside (in myelin sheeth) c. AR |
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Lysosomal storage diseases
a. deficient enzyme b. accumulated substrate c. inheritance patient presents with -central and peripheral demylination --> ataxia, dementia |
metachromatic leukodystrophy
a. arylsulfatase A b. cerebroside sulfate c. AR |
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Mucopolysaccharidoses
a. deficient enzyme b. accumulated substrate c. inheritance Patient presents with -developmental delay -gargoylism -airway obstruction -corneal clouding -hepatosplenomegaly |
Hurler's
a. a-L-iduronidase b. heparan sulfate, dermatan sulfate c. AR |
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Mucopolysaccharidoses
a. deficient enzyme b. accumulated substrate c. inheritance patient has -mild hurler's symptoms -aggressive behavior -No corneal clouding |
Hunter's
a. iduronate sulfatase b. heparan sulfate, dermatan sulfate c. XR "Hunters see clearly (no corneal clouding) and aim for the X (X-linked recessive)" |
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Tay Sachs, Niemann-ick, Gaucher's have higher incidence in what population
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Ashkenazi Jew
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Fatty acid synthesis
a. how does acetyl CoA get from mitochondrial matrix to cell cytoplasm b. what happens to acetyl CoA inside cytoplasm c. what is final product |
a. acetyl-CoA converted to citrate --> citrate shuttle to cytoplasm
b. acetyl CoA-->malonyl CoA (CO2 from biotin) malonyl CoA --> FA synth c. Palmitate (16C) SYtrate = SYnthesis |
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FA degradation
a. what happens to FA in the cytoplasm first b. how does it cross from cytoplasm to inner membrane c. what inhibits this shuttling d. what happens when it is in the mitochondrial matrix |
a. FA + CoA --> acyl CoA (FA CoA synthetase)
b. Conjugated to carnitine (carnitine acyl transferase I) --> carnitine shuttle --> unconjugated from carnitine c. inhibited by malonyl CoA d. b-oxidation of acyl-CoA --> ketone bodies, TCA cycle |
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Patient has toxic accumulation of long chain fatty acids in cell cytoplasm
-weakness -hypotonia -hypoketotic hypoglycemia dx. path. |
carnitine deficiency
inability to transport long chain FAs into mitochondria for oxidation --> accumulation |
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patient has
-high dicarboxylic acids -low glucose -low ketones dx? |
acyl-CoA dehydrogenase deficiency
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Ketone bodies
what are 2 forms? where are they produced? where are they used? |
acetoacetate, b-hydroxybutyrate
produced in liver Used in heart and brain |
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a. How does fasted state or diabetic ketoacidosis inhibit TCA cycle?
b. Chronic alcholoism? |
a. oxaloacetate devoted to gluconeogenesis, cannot serve as an intermediate in TCA
b. excess NADH shunts oxaloacetate to malate |
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Ketone bodies
made from what? what is it metabolized to in the brain? excreted? |
made from HMG-CoA
metabolized in brain to 2 Acetyl-CoA molecules excreted in urine |
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2 tests for ketone bodies
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1. fruity breath (acetone)
2. urine test for ketones (but does not detect b-hydroxybutyrate) |
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Metabolic fuel use
how much energy a. 1 g protiein or carbs b. 1 g fat |
a. 4kcal
b. 9kcal |
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Metabolic fuel use
where does energy come from for 100 m sprint (seconds) |
stored ATP, creatine phosphate, anaerobic glycolysis
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Metabolic fuel use
where does energy come from for 100 m run (minutes) |
stored ATP, creatine phosphate, anaerobic glycolysis, oxidative phosphorylation
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Metabolic fuel use
where does energy come from for a marathon (hrs) |
Glycogen and FFA oxidation, glucose conserved for final sprint
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Fasting and starvation
what are your body's priorities |
supply glucose to brain and RBCs, preserve protein
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Fed state
where does body get energy? What does insulin do? |
glycolysis, aerobic respiration
Insulin stimulates storage of lipids, proteins, and glycogen |
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Fasting state (between meals)
where does body get energy? Role of glucagon/epi |
hepatic glycogenolysis (major)
hepatic gluconeogenesis adipose release of FFA (minor) glucagon, epi stimulate use of fuel reserves |
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How is blood glucose maintained in a 1-3 day starve (4 steps)
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1. hepatic glycogenolysis (reserves depleted after 1 day)
2. adipose release of FFA 3. muscle and liver shift fuel use from glucose to FFA 4. hepatic gluconeogenesis from peripheral tissue lactate and alanine, and from adipose tissue glycerol and propionyl-CoA (odd chain FFA) |
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How do you get energy after day 3 of starvation?
what deterimines survival? |
adipose stores, then protein degradation to make ketone bodies (leads to organ failure and death)
adipose stores determines survivial time |
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Cholesterol synth
Rate limiting step? |
HMG CoA reductase
HMG-CoA --> mevalonate |
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What happens to 2/3 of plasma cholesterol
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esterified by LCAT
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Role of statins
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inhibit HMG-CoA reductase
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Lipid Transport
What is responsible for degradation of dietary TG in small intestine |
pancreatic lipase
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Lipid Transport
Responsible for degradation of TG circulating in chylomicrons and VLDLs |
Lipoprotein lipase
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Lipid Transport
Degrades TG remaining in IDL |
Hepatic TG lipase
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Lipid Transport
Degrades TG stored in adipocytes |
Hormone sensitive lipase
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Lipid Transport
Role of LCAT |
Catalyzes esterification of cholesterol, making it more hydrophobic
Allows it to be sequestered in HDL, making HDL mature |
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Lipid Transport
What are 2 pathways for mature HDL to deliver its cholesterol |
1. Directly to Liver
2. Transfers cholesterol to VLDL, IDL, and LDL via CETP |
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Lipid Transport
What is cholesterol ester transfer protein |
Allows HDL to give its cholesterol to VLDL, IDL, and LDL in exchange for TG
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Apolipoproteins
a. function b. where A1 |
A1 Activates LCAT
HDL |
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Apolipoproteins
a. function b. where B-100 |
B-100 Binds to LDL receptor, mediates VLDL secretion
VLDL, IDL, LDL |
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Apolipoproteins
a. function b. where C-II |
C-II = Cofactor for LPL
Chylomicron, VLDL |
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Apolipoproteins
a. function b. where B-48 |
Mediates chylomicron secretion
chylomicrons |
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Apolipoproteins
a. function b. where E |
E mediates Extra (remnant) uptake
Chylomicron, VLDL, IDL |
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Lipoprotein functions
chylomicrons a. secreted from where b. 2 places for its products c. apolipoproteins |
a. intestinal epithelial cells
b. Delivers cholesterol to liver (chylomicron remnants), delivers TGs to peripheral tissue c. B-48, A-IV, C-II, E |
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Lipoproteins
Which 2 carry the most cholesterol and where do they take them |
HDL takes cholesterol from periphery to liver
LDL takes cholesterol from liver to peripheral tissues |
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Lipoproteins
VLDL a. secreted by b. where does it deliver c. apolipoproteins |
a. liver
b. delivers hepatic TGs to peripheral tissue c. B-100, C-II, E |
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Lipoproteins
LDL a. how is it formed b. how is it taken up c. what does it deliver d. apolipoproteins |
a. LPL modification of VLDL
b. receptor-mediated endocytosis c. delivers cholesterol to peripheral tissues d. B-100 |
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IDL
a. how is it formed b. what does it deliver c. what happens after delivery d. apolipoproteins |
a. Degradation of VLDL
b. Delivers TG and cholesterol to liver c. degraded to LDL at liver d. B-100, E |
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HDL
a. secreted by (2) b. Jobs (2) |
a. secreted by liver and intestine
b. reverse cholesterol transport from periphery to liver repository for apoC and E (for chylomicron and chylomicron metabolism) |
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Patient comes in with
-pancreatitis -hepatosplenomegaly -eruptive xanthomas -NO increased atherosclerosis Blood shows high TG and cholesterol dx. what is increased? |
Type I hyperchylomicronemia
Chylomicrons in blood increased |
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Patient comes in with
-accelerated atherosclerosis -achilles tendon xanthomas -corneal arcus blood shows high cholesterol only a. dx? genetics? b. what is missing c. what is increased? |
a. Type IIa familial hypercholesterolemia (aut. dom)
b. missing LDL receptor c. high LDL |
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Patient comes in with
-pancreatitis -high TG in blood type of dyslipidemia? What is increased |
Type IV hypertriglyceridemia
VLDL increased |
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What is wrong in type I hyperchylomicronemia to cause elevated blood TG and cholesterol
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LPL deficiency or altered apolipoprotein CII
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Baby presents with
-failure to thrive -steatorrhea -acanthocytosis -ataxia -night blindness Intestinal biopsy shows lipid accumulation within enterocytes a. dx b. path c. genetics |
a. abeta-lipoproteinemia
b. Inability to synthesize lipoproteins due to deficiencies in apoB48 and apoB100 c. aut recessive |
