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114 Cards in this Set

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Why are triglycerides the major storage of energy?
Because they're reduced and dehydrated - allows them to be oxidized a lot and compact.
What is the yield of energy from fat metabolism?
9 kcal/g

Protein/carb = 4
What aids in the digestion of lipids?
-Bile salts/micelles
-Pancreatic lipases
What are bile salts?
Amphipathic lipids made in the liver/secreted from gallbladder.
Why are micelles soluble?
They orient the ester of triglycerides so that it points into aqueous environment.
What digests lipids in micelles?
Pancreatic lipase - makes monoacylglycerol + tryglyc
What is the condition where bile salts are low?
Steatorrhea - greasy feces
What happens to micelles w/ digestion products?
Uptake by mucosal cell.
What happens to the fat once in mucosal cell?
Incorporated into chylomicrons
Where do chylomicrons go?
Into lymphatics -> blood
What happens to chylomicrons in the blood?
Membrane bound LIPOPROTEIN LIPASE binds them at FAt and Muscle.
What does LPL do?
Chew up Fat into monoacylglyc and FA - allows tissue uptake.
What happens to the triglyc in
-Fat
-Muscle
Fat stores it
Muscle uses it
What are the 3 stages inherent to Utilizing FFA for energy?
1. Mobilization
2. Activation/transport to mito
3. Oxidation
What does mobilization of triglyceride consist of?
Degradation to FA + glycerol
What other than degradation has to be done to mobilize fat?
-Release from Adipose
-Transport to tissue
Why do mobilized FA's have to be transported into mitochondria?
B/c that's where B-oxidation enzymes are.
What is the end product of FA oxidation and what can it participate in?
AcCoA - in the TCA
What is mobilizing stored FA called?
Lipolysis
What catalyzes the rate-limiting step of lipolysis?
HSL - hormone sensitive lipase
Why is this hormone SOOOO IMPORTANT?
B/c it regulates all of lipolysis and fa metabolism.
What regulates HSL?
Hormones - Glu:ins ratio
What will activate HSL?
A high Glu:Ins ratio will activate the cAMP-dependent PKA casacade and thus HSL
What is also activated by this cascade?
Glycogenolysis (glycogen phosphatase/synthase)
What is an important point to remember about HSL's site?
It is only in adipocytes - not in muscle cells.
What clinical disease is caused by aberrent HSL regulation?
Diabetes type II
What is the problem in Diab II?
Hypertriglyceridemia - overactive Hormonse sens lipase
What does the reaction of HSL produce?
Diacylglycerol; other lipases cleave additional FA's.
What protein transports free fatty acids to the tissues that need energy?
Albumin
What happens after cellular uptake of free FA?
They can get into mito outer membrane, but not the inner.
What happens to Glycerol released by breakdown of fat?
-Liver adsorbs it (v. soluble)
-Phosphorylates/oxidizes it
-Isomerizes to G3P
What can G3P do?
Enter glycolysis or GLUCONEOGENESIS (depending on stress levels, etc.)
What has to happen for FA's to get into the mito matrix?
Activation - like charging tRNA
How are FA's charged? (2 steps)
1. ATP makes them Acyl Adenylate (release PPi, subseq. hydrolys)
2. Acyl Adenylate + CoASH makes AcylCoA + AMP
Where does the CoASH for activating FA's come from?
Cytosolic pool
What enzyme catalyzes activation of FA for mito uptake?
Acyl CoA Synthetase (AS)
Where is AS located?
On outer mito membrane.
How do activated long chain FAs get into mito matrix?
Via conjugation to Carnitine
What doesn't need conjugation?
Medium chain - 8-10C
What is Carnitine derived from?
Lysine
What is carnitine generated from?
Trimethyllysine from proteins
What is the methyl group donor that modifies lysine to make Carnitine?
SAM
What is the major source of Carnitine even though the liver can keep us supplied?
Diet - meat
What enzyme accomplishes this conjugation step, and where?
Carnitine acyltransferase I CPTI
-on outer mito membrane (inner side)
What happens to the fatty acid in this conjugation?
Goes from AcylCoA to AcylCarnitine
If the liver is in the middle of FA Biosynthesis, how is futile fatty oxidation avoided?
Malonyl CoA inhibits CPT1
What specific CPTI does malonyl CoA inhibit?
Liver specific
What happens Acyl-carnitine?
CT translocates it across the inner mito membrane!
Where is CT?
Carnitine/Acylcarnitine Translocase is on the inner side of the inner mito membrane.
How does carnitine get back into the intermembrane space?
CT also translocates it back.
What does impairment of the Carnitine cycle result in? Symptoms?
Impaired utilization of long chain fatty acids for E prodctn
-Muscle cramps
-Severe weakness -> death
What did Knoops experiment demonstrate?
-Even and odd # FA undergo different oxidation mechanisms
-Oxidation occurs in 2-C incrmts from B-carbon end.
What does B-oxidation accomplish in broad terms?
Converts aliphatic carbon chain to acetylated units that can be sent to TCA
What is the B-oxidation process?
Reverse of synthesis
What are the steps of B-oxid?
1. Oxidation - make doub bond
2. Hydration - make alcohol
3. Oxidation - make ketone
4. Cleave AcylCoA -> AcCoA
What are the enzymes involved in beta oxidation?
Family of AcylCoA Dehydrogenases
What is the main thing to remember about AcylCoA dehydrogenases?
-All are Flavoproteins with FAD as a prosthetic group!!
What is the consequence of B-oxidation enzymes having FAD as a prostethic group?
They donate the electrons from oxidation directly to ETC!!! (via ETF)
What TCA reaction is b-oxidation comparable to?
Succinate dehydrogenase - also donates 2 e- directly to FADH2 to ETC.
What complex in ETC gets these electrons?
Complex II - hence not as much energy as for NADH, but still some.
What is the most common inherited Acyl-CoA dehydrogenase deficiency?
MCAD
What are the symptoms of MCAD?
-Vomiting
-Lethargy
-Coma after fasting >12 hrs
What enzyme catalyzes the hydration of the double bond created by oxidation step 1?
Enoyl CoA hydratase
What does Enoyl CoA hydratase produce?
B-hydroxyacyl CoA - this is the molecule with an OH on the beta carbon that can be BETA OXIDIZED
What catalyzes step 3 of beta oxidation?
Beta-hydroxyacyl CoA dehydrogenase
2 important points about B-hydroxyacyl CoA dehydrog:
1. Only recognizes L-isomer of b-hydroxyacyl CoA
2. Makes NADH to give right to ETC
What enzyme catalyzes the last step of beta oxidation?
B-ketothiolase
What does the entire b-oxidtn process culminate in?
Thiolytic cleavg of Acetoacetyl-CoA to make 2 AcCoA
So what is the net yield of b-oxidation of Palmitoyl CoA?
8 AcCoA
7 FADH2
7 NADH2
7 H+
How is AcCoA used for energy in
-Muscle
-Liver
Muscle - TCA cycle

Liver - Ketogenesis
What are ketone bodies useful for?
Transport to brain/muscle for final oxidation
What does oxidation of ODD chain fatty acids ultimately yield?
-one AcCoA
-one Propionyl CoA (3 carbon)
What happens to propionyl CoA?
Further oxidation to Succinyl CoA
What will deficiency in the enzymes needed for Succinyl CoA oxidation result in?
Metabolic acidosis and developmental retardation.
What is the important point about Methylmalonyl CoA mutase?
It is one of only 2 enzymes that use Adenosylcobalamin coenzyme.
What is Adenosylcobalamine a derivative of?
Vitamin B12
Why is it good that Propionyl CoA can be oxidized to Succinyl CoA?
B/c that can be put into the TCA cycle.
What additional enzymes are required for b-oxidation of unsaturated fatty acids?
-Isomerase: to change cis double bonds to trans
-Reductase: to change some 2-double bond molecules to one.
Why does the double bond have to be made trans in order for acyl CoA dehydrogenase to work on it?
B/c oxidation involves making double bonds; can't make 2 double bonds on the same C.
What enzyme overcomes this problem?
Enoyl CoA isomerase
What can't Enoyl CoA isomerase take care of?
Molecules like Linolenic CoA that have 2 adjacent double bonds w/ a CH2 between them.
What enzyme CAN take care of this problem?
2,4-Dienoyl CoA reductase
What does 2,4-dienoyl CoA reductase require in order to allow beta oxid to continue?
NADPH
What polyunsaturated FAs are handled by
-the isomerase?
-the reductase?
Isomerase = ODD

Reductase = EVEN
What 2 minor pathways can accomplish oxidation of FAs?
-Alpha
-Omega
What is alpha oxidation important in?
Metabolism of branched chain FA in the diet
Where does a-oxidation primarily occur?
In peroxisomes
What is Phytanic acid in?
Dairy proucts and animal fat
What disease has deficient enzyme needed for a-oxidation of Phytanic acid?
Refsum's disease
What deficits occur in Refsum's disease?
-Neurological problems
-Retinitis pigmentosa
-Peripheral neuropathy
-Cerebellar ataxia
Where does omega oxidation occur?
Endoplasmic reticulum
When does W-oxidation become important?
When Beta is deficient (ie MCAD deficiency, CPT deficiency)
What is the usual purpose of generating AcCoA from FA oxidn?
To send it to the TCA cycle
What can limit the use of AcCoA by the TCA cycle?
Availability of Oxaloacetate to condense w/ it and form Citrate.
Why would Oxaloacetate not be available?
If not enough pyruvate were available for Pyruvate carboxylase to form it.
What conditions would cause this to be the case?
Fasting, not utilizing glucose correctly (diabetes)
Why is oxaloacetate not available in fasting conditions?
It is shunted to gluconeogenesis.
What will the AcCoA generated by fatty acid oxidation then do?
Form ketones - ketogenesis
Where does Ketogenesis take place?
Liver mitochondrial matrix
What ketone bodies are made?
-B-hydroxybutyrate
-Acetoacetate
What is the first step of ketogenesis/what catalyzes it?
Condensation of 2 AcCoA
-B-ketothiolase
What happens to Acetoacetyl CoA made in step 1?
Added to a 3rd AcCoA to make HMG CoA
What happens to HMG CoA?
Cleavage/loss of AcCoA to make Acetoacetic Acid
What enzymes catalyze these last 2 steps?
-HMG CoA Synthetase
-HMG CoA Lyase
What are cytosolic isoforms of these enzymes active in?
Cholesterol biosynthesis (block 3)
What can happen to Acetoacetate and what determines this step?
Reduction to B-hydroxybutyrate - depends on NAD/NADH ratio;
What will happen to Acetoacetate under pathologicaly high conditions?
It will spontaneously decarboxylate to acetone and be smelled on the breath.
Why can production of ketone bodies be good (if not patholg)?
It allows the liver to keep B-oxidizing FA's by preventing product AcCoA build up in the absence of oxaloacetate.
And why is oxaloacetate absent?
Pyruvate -> oxaloacetate is being shunted to gluconeogenesis
How are ketones useful in themselves?
They are water-sol and can go to tissues for use
What tissues can use ketone bodies in the absence of glu?
-Brain (via adapting)
-RBCs
How do tissues use ketones? (pathway)
1. Activation by Succinyl CoA
2. Loss of Succinate
3. Loss of CoASH
4. Makes AcetylCoA
What enzyme catalyzes the important step of activation?
3-ketoacyl-CoA transferase
Where is this enzyme NOT?
In liver - thus ketone genesis in the liver won't be futile.