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114 Cards in this Set
- Front
- Back
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Why are triglycerides the major storage of energy?
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Because they're reduced and dehydrated - allows them to be oxidized a lot and compact.
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What is the yield of energy from fat metabolism?
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9 kcal/g
Protein/carb = 4 |
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What aids in the digestion of lipids?
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-Bile salts/micelles
-Pancreatic lipases |
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What are bile salts?
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Amphipathic lipids made in the liver/secreted from gallbladder.
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Why are micelles soluble?
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They orient the ester of triglycerides so that it points into aqueous environment.
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What digests lipids in micelles?
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Pancreatic lipase - makes monoacylglycerol + tryglyc
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What is the condition where bile salts are low?
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Steatorrhea - greasy feces
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What happens to micelles w/ digestion products?
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Uptake by mucosal cell.
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What happens to the fat once in mucosal cell?
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Incorporated into chylomicrons
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Where do chylomicrons go?
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Into lymphatics -> blood
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What happens to chylomicrons in the blood?
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Membrane bound LIPOPROTEIN LIPASE binds them at FAt and Muscle.
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What does LPL do?
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Chew up Fat into monoacylglyc and FA - allows tissue uptake.
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What happens to the triglyc in
-Fat -Muscle |
Fat stores it
Muscle uses it |
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What are the 3 stages inherent to Utilizing FFA for energy?
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1. Mobilization
2. Activation/transport to mito 3. Oxidation |
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What does mobilization of triglyceride consist of?
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Degradation to FA + glycerol
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What other than degradation has to be done to mobilize fat?
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-Release from Adipose
-Transport to tissue |
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Why do mobilized FA's have to be transported into mitochondria?
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B/c that's where B-oxidation enzymes are.
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What is the end product of FA oxidation and what can it participate in?
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AcCoA - in the TCA
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What is mobilizing stored FA called?
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Lipolysis
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What catalyzes the rate-limiting step of lipolysis?
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HSL - hormone sensitive lipase
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Why is this hormone SOOOO IMPORTANT?
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B/c it regulates all of lipolysis and fa metabolism.
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What regulates HSL?
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Hormones - Glu:ins ratio
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What will activate HSL?
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A high Glu:Ins ratio will activate the cAMP-dependent PKA casacade and thus HSL
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What is also activated by this cascade?
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Glycogenolysis (glycogen phosphatase/synthase)
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What is an important point to remember about HSL's site?
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It is only in adipocytes - not in muscle cells.
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What clinical disease is caused by aberrent HSL regulation?
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Diabetes type II
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What is the problem in Diab II?
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Hypertriglyceridemia - overactive Hormonse sens lipase
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What does the reaction of HSL produce?
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Diacylglycerol; other lipases cleave additional FA's.
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What protein transports free fatty acids to the tissues that need energy?
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Albumin
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What happens after cellular uptake of free FA?
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They can get into mito outer membrane, but not the inner.
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What happens to Glycerol released by breakdown of fat?
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-Liver adsorbs it (v. soluble)
-Phosphorylates/oxidizes it -Isomerizes to G3P |
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What can G3P do?
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Enter glycolysis or GLUCONEOGENESIS (depending on stress levels, etc.)
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What has to happen for FA's to get into the mito matrix?
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Activation - like charging tRNA
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How are FA's charged? (2 steps)
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1. ATP makes them Acyl Adenylate (release PPi, subseq. hydrolys)
2. Acyl Adenylate + CoASH makes AcylCoA + AMP |
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Where does the CoASH for activating FA's come from?
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Cytosolic pool
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What enzyme catalyzes activation of FA for mito uptake?
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Acyl CoA Synthetase (AS)
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Where is AS located?
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On outer mito membrane.
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How do activated long chain FAs get into mito matrix?
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Via conjugation to Carnitine
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What doesn't need conjugation?
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Medium chain - 8-10C
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What is Carnitine derived from?
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Lysine
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What is carnitine generated from?
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Trimethyllysine from proteins
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What is the methyl group donor that modifies lysine to make Carnitine?
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SAM
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What is the major source of Carnitine even though the liver can keep us supplied?
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Diet - meat
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What enzyme accomplishes this conjugation step, and where?
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Carnitine acyltransferase I CPTI
-on outer mito membrane (inner side) |
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What happens to the fatty acid in this conjugation?
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Goes from AcylCoA to AcylCarnitine
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If the liver is in the middle of FA Biosynthesis, how is futile fatty oxidation avoided?
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Malonyl CoA inhibits CPT1
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What specific CPTI does malonyl CoA inhibit?
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Liver specific
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What happens Acyl-carnitine?
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CT translocates it across the inner mito membrane!
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Where is CT?
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Carnitine/Acylcarnitine Translocase is on the inner side of the inner mito membrane.
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How does carnitine get back into the intermembrane space?
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CT also translocates it back.
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What does impairment of the Carnitine cycle result in? Symptoms?
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Impaired utilization of long chain fatty acids for E prodctn
-Muscle cramps -Severe weakness -> death |
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What did Knoops experiment demonstrate?
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-Even and odd # FA undergo different oxidation mechanisms
-Oxidation occurs in 2-C incrmts from B-carbon end. |
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What does B-oxidation accomplish in broad terms?
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Converts aliphatic carbon chain to acetylated units that can be sent to TCA
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What is the B-oxidation process?
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Reverse of synthesis
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What are the steps of B-oxid?
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1. Oxidation - make doub bond
2. Hydration - make alcohol 3. Oxidation - make ketone 4. Cleave AcylCoA -> AcCoA |
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What are the enzymes involved in beta oxidation?
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Family of AcylCoA Dehydrogenases
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What is the main thing to remember about AcylCoA dehydrogenases?
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-All are Flavoproteins with FAD as a prosthetic group!!
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What is the consequence of B-oxidation enzymes having FAD as a prostethic group?
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They donate the electrons from oxidation directly to ETC!!! (via ETF)
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What TCA reaction is b-oxidation comparable to?
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Succinate dehydrogenase - also donates 2 e- directly to FADH2 to ETC.
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What complex in ETC gets these electrons?
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Complex II - hence not as much energy as for NADH, but still some.
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What is the most common inherited Acyl-CoA dehydrogenase deficiency?
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MCAD
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What are the symptoms of MCAD?
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-Vomiting
-Lethargy -Coma after fasting >12 hrs |
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What enzyme catalyzes the hydration of the double bond created by oxidation step 1?
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Enoyl CoA hydratase
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What does Enoyl CoA hydratase produce?
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B-hydroxyacyl CoA - this is the molecule with an OH on the beta carbon that can be BETA OXIDIZED
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What catalyzes step 3 of beta oxidation?
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Beta-hydroxyacyl CoA dehydrogenase
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2 important points about B-hydroxyacyl CoA dehydrog:
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1. Only recognizes L-isomer of b-hydroxyacyl CoA
2. Makes NADH to give right to ETC |
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What enzyme catalyzes the last step of beta oxidation?
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B-ketothiolase
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What does the entire b-oxidtn process culminate in?
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Thiolytic cleavg of Acetoacetyl-CoA to make 2 AcCoA
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So what is the net yield of b-oxidation of Palmitoyl CoA?
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8 AcCoA
7 FADH2 7 NADH2 7 H+ |
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How is AcCoA used for energy in
-Muscle -Liver |
Muscle - TCA cycle
Liver - Ketogenesis |
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What are ketone bodies useful for?
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Transport to brain/muscle for final oxidation
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What does oxidation of ODD chain fatty acids ultimately yield?
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-one AcCoA
-one Propionyl CoA (3 carbon) |
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What happens to propionyl CoA?
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Further oxidation to Succinyl CoA
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What will deficiency in the enzymes needed for Succinyl CoA oxidation result in?
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Metabolic acidosis and developmental retardation.
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What is the important point about Methylmalonyl CoA mutase?
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It is one of only 2 enzymes that use Adenosylcobalamin coenzyme.
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What is Adenosylcobalamine a derivative of?
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Vitamin B12
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Why is it good that Propionyl CoA can be oxidized to Succinyl CoA?
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B/c that can be put into the TCA cycle.
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What additional enzymes are required for b-oxidation of unsaturated fatty acids?
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-Isomerase: to change cis double bonds to trans
-Reductase: to change some 2-double bond molecules to one. |
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Why does the double bond have to be made trans in order for acyl CoA dehydrogenase to work on it?
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B/c oxidation involves making double bonds; can't make 2 double bonds on the same C.
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What enzyme overcomes this problem?
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Enoyl CoA isomerase
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What can't Enoyl CoA isomerase take care of?
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Molecules like Linolenic CoA that have 2 adjacent double bonds w/ a CH2 between them.
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What enzyme CAN take care of this problem?
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2,4-Dienoyl CoA reductase
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What does 2,4-dienoyl CoA reductase require in order to allow beta oxid to continue?
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NADPH
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What polyunsaturated FAs are handled by
-the isomerase? -the reductase? |
Isomerase = ODD
Reductase = EVEN |
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What 2 minor pathways can accomplish oxidation of FAs?
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-Alpha
-Omega |
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What is alpha oxidation important in?
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Metabolism of branched chain FA in the diet
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Where does a-oxidation primarily occur?
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In peroxisomes
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What is Phytanic acid in?
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Dairy proucts and animal fat
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What disease has deficient enzyme needed for a-oxidation of Phytanic acid?
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Refsum's disease
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What deficits occur in Refsum's disease?
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-Neurological problems
-Retinitis pigmentosa -Peripheral neuropathy -Cerebellar ataxia |
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Where does omega oxidation occur?
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Endoplasmic reticulum
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When does W-oxidation become important?
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When Beta is deficient (ie MCAD deficiency, CPT deficiency)
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What is the usual purpose of generating AcCoA from FA oxidn?
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To send it to the TCA cycle
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What can limit the use of AcCoA by the TCA cycle?
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Availability of Oxaloacetate to condense w/ it and form Citrate.
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Why would Oxaloacetate not be available?
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If not enough pyruvate were available for Pyruvate carboxylase to form it.
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What conditions would cause this to be the case?
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Fasting, not utilizing glucose correctly (diabetes)
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Why is oxaloacetate not available in fasting conditions?
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It is shunted to gluconeogenesis.
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What will the AcCoA generated by fatty acid oxidation then do?
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Form ketones - ketogenesis
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Where does Ketogenesis take place?
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Liver mitochondrial matrix
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What ketone bodies are made?
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-B-hydroxybutyrate
-Acetoacetate |
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What is the first step of ketogenesis/what catalyzes it?
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Condensation of 2 AcCoA
-B-ketothiolase |
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What happens to Acetoacetyl CoA made in step 1?
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Added to a 3rd AcCoA to make HMG CoA
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What happens to HMG CoA?
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Cleavage/loss of AcCoA to make Acetoacetic Acid
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What enzymes catalyze these last 2 steps?
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-HMG CoA Synthetase
-HMG CoA Lyase |
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What are cytosolic isoforms of these enzymes active in?
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Cholesterol biosynthesis (block 3)
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What can happen to Acetoacetate and what determines this step?
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Reduction to B-hydroxybutyrate - depends on NAD/NADH ratio;
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What will happen to Acetoacetate under pathologicaly high conditions?
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It will spontaneously decarboxylate to acetone and be smelled on the breath.
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Why can production of ketone bodies be good (if not patholg)?
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It allows the liver to keep B-oxidizing FA's by preventing product AcCoA build up in the absence of oxaloacetate.
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And why is oxaloacetate absent?
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Pyruvate -> oxaloacetate is being shunted to gluconeogenesis
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How are ketones useful in themselves?
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They are water-sol and can go to tissues for use
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What tissues can use ketone bodies in the absence of glu?
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-Brain (via adapting)
-RBCs |
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How do tissues use ketones? (pathway)
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1. Activation by Succinyl CoA
2. Loss of Succinate 3. Loss of CoASH 4. Makes AcetylCoA |
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What enzyme catalyzes the important step of activation?
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3-ketoacyl-CoA transferase
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Where is this enzyme NOT?
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In liver - thus ketone genesis in the liver won't be futile.
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