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94 Cards in this Set
- Front
- Back
What is the source of all carbons for fatty acids?
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acetyl CoA
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What is required for fatty acid synthesis?
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NADPH, ATP
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Where does fatty acid synthesis occur?
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cytosol
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Acetyl CoA is transported to the cytosol for fatty acid synthesis in the form of:
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citrate
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The ctirate-pyruvate shuttle generates what important cofactors:
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NAD+ required for glycolysis and NADPH required for fatty acid synthesis
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What is the rate limiting enzyme for fatty acid biosynthesis?
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Acetyl CoA carboxylase
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The activated intermediate for fatty acid synthesis is:
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malonyl CoA
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What is the cofactor for acetyl CoA carboxylase?
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biotin
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Malonyl CoA inhibits:
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entry of fatty acids into mitochondria; therefore, inhibits b-oxidation
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ACC-1 found in:
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cytosol of liver & adipose; produces malonyl CoA for fatty acid synthesis
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ACC-2 found in:
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mitochondrial membrane of muscle & liver; produces malonyl CoA for inhibition of B-oxidation in fed state; ensures these tissues primarily use glucose in fed state
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Fatty acid synthase
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- 2 identical subunits
- 7 catalytic sites - catalyses all remaining reactions to convert malonyl groups to fatty acid |
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Binding site for malonate on fatty acid synthase is:
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Phosphopantothenate group closely related to coenzyme A and comes from pantothenic acid
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1st step in fatty acid synthase reaction is:
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transfer of malonate from malonyl CoA to phosphopantotheinate on 1 subunit and acetyl group from acetyl CoA to cysteine residue on other subunit
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How many cycles of malonyl CoA addition to fatty acid ensues?
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7 cycles until 16-carbon acyl residue produced
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Final step in fatty acid synthesis is:
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hydrolysis to release chain as free palmitate
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Chain terminating process in fatty acid synthase dictated by:
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thiolase activity of 1 of domains of fatty acid synthase
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Fatty acids are modified by:
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elongating carbon chain & introducing double bonds
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What enzymes introduce double bonds into fatty acid residues?
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Desaturases
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Desaturases are very specific for:
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the position at which they introduce a double bond
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Desaturases require:
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COPPER
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What 4 steps are repeated in order for fatty acid biosynthesis?
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Condensation, reduction, dehydration, reduction
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Why are linoleic and linolenic fatty acids essential?
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We lack enzymes to introduce double bonds at the omega 3 and omega 6 positions
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What is a potential reason stearic acid doesn't raise cholesterol levels?
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It can be converted to unsaturated oleic aicd through remodeling
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Acetyl CoA carboxylase is activated at the cellular level (in cytosol) by:
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Citrate
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Acetyl CoA carboxylase is inhibited at the cellular level by:
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Palmitoyl CoA
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Activation of acetyl CoA carboxylase occurs when the enzyme is:
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Dephosphorylated
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Acetyl CoA carboxylase is activated at the whole body level by:
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Insulin
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Acetyl CoA carboxylase is inhibited at the whole body level by:
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Glucagon, Epinephrine
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Phosphorylation of acetyl CoA carboxylase occurs through activation of:
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cAMP-dependent protein kinase (PKA)
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Insulin dephosphorylates acetyl CoA carboxylase through action of:
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protein phosphatase
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What can partially activate acetyl CoA carboxylase even in absence of insulin?
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Citrate
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What can partially inactivate acetyl CoA carboxylase even in presence of insulin?
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Palmitoyl CoA
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How does lactate contribute to triglyceride overproduction associated with Type 2 diabetes?
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Lactate provides OAA & FAs the acetyl CoA needs for citrate formation; citrate can partially activate acetyl CoA carboxylase
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AMP-PK
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phosphorylates and inactivates acetyl CoA carboxylase
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AMP-PK is active when:
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AMP is high (fasting and exercise)
it decreases fatty acid synthesis and increases beta-oxidation |
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AMP-PK is inactive when:
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glucose is high
- fed state and type 2 diabetes - it increases fatty acid synthesis and decreases beta-oxidation |
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What hormones, etc increase transcription of enzymes for fatty acid synthesis?
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Insulin, adipokines
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Why might unsaturated fats lower serum triglyceride levels?
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They seem to inhibit rate of transcription of enzymes associated with fatty acid synthesis.
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Transcription factor SREBP-1c upregulates the genes for which enzymes?
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Acetyl CoA carboxylase, fatty acid synthase, gly-3p acyltransferase
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How do fibrate drugs decrease the levels of enzymes associated with fatty acid synthesis?
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By activating PPAR alpha
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PPAR gamma controls:
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adipocyte differentiation, insulin sensitivity
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PPAR alpha:
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down-regulates fatty acid & TG synthesis, up-regulates B-oxidation
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What factors cause the liver to overproduce VLDL in Type 2 diabetes?
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Adipokines activate ACC-2; lactate produces OAA and acetyl CoA which are converted to citrate which also activates ACC-2
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Synthesis of triglycerides and compound lipids involves formation of:
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Phosphatidic acid
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Glycerol kinase
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converts glycerol to glycerol 3 phosphate in the liver
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In fed state, what intermediate is major source of 3 C backbone needed for triglyceride synthesis?
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DHAP
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In fasting state, hydrolysis of stored triglycerides in adipose results in:
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Release of glycerol
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Glyceroneogenesis
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Tissues convert glucose and amino acids to DHAP in fasting state; DHAP can be converted to glycerol-3-phosphate
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What enzyme is required for triglyceride formation?
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Glycerol 3-Pi acyl transferase
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Glycerol 3-Pi acyl transferase
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Catalyzes addition of fatty acids to glycerol 3-phosphate backbone
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Triglycerides can be formed from either:
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DHAP or glycerol phosphate
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Glycerol phosphate can be formed by either:
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Phosphorylation of glycerol (glycerol kinase); glyceroneogenesis in fasting state; reduction of DHAP in fed state
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Beta-oxidation occurs where?
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All tissues with mitochondria
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What are 2 stages of fatty acid oxidation?
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1. All carbons oxidized to acetyl CoA
2. Acetyl CoA oxidized by citric acid cycle |
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How do hormones regulate HSL?
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Glucagon/epinephrine/glucocorticoids activate; insulin inhibits
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How are free fatty acids transported in blood?
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Bound to serum albumin
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What proteins appear to be regulated in parallel with hormone-sensitive lipase?
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Perilipin and adipose triglyceride lipase
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What protein does transport of fatty acids into the cell require?
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Fatty acid transport protein
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What enzyme catalyzes the formation of acyl CoA from free fatty acids?
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Acyl CoA synthetase
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What enzyme catalyzes formation of acyl carnitine on outer mitochondrial membrane?
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CPT-I
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What enzyme catalyzes formation of acyl CoA on matrix side of mitochondira?
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CPT-II
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What effect does exercise have on fatty acid oxidation?
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Increases CPT-I levels; Increases # of mitochondria
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What steps are involved in fatty acid oxidation?
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Oxidation, Hydration, Oxidation, Thiolysis
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Fatty acid oxidation produces:
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FADH2 and NADH
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Peroxisomes primarily perform oxidation on fatty acids of length:
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> C16; but definitely must be > 8
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Peroxisomes break down long chain fatty acids to:
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octanoyl CoA (C8) and acetyl CoA
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The first step in peroxisomal fatty acid oxidation utilizes what enzyme:
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acyl CoA oxidase
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Hormone-sensitive lipase hydrolyzes triglycerides to:
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free fatty acids and glycerol
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Malonyl Co-A inhibits:
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CPT-I
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What is the ultimate precursor for fatty acid synthesis?
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Citrate
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What drives beta-oxidation during fasting and starvation?
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mass action
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Levels of B-oxidation enzymes is regulated by:
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PPAR alpha
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PPAR alpha is activated by:
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omega 3 long chain polyunsaturated fatty acids
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PPAR alpha inactivated by:
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insulin (by way of MAPK) and glucose (by way of low AMP-PK levels)
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PPAR alpha increases levels of:
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fatty acid transport protein, acyl CoA synthetase, acyl CoA oxidase, CPT-I, other mitochondrial B-oxidation enzymes
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What is the mechanism of action of fibrate drugs?
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Activate PPAR alpha to stimulate B-oxidation
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What is the effect of exercise on PPAR alpha?
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Doubles PPAR alpha levels in muscle cells
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Where does ketone body synthesis occur?
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Exclusively in liver mitochondria
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Liver mitochondria have high concentrations of:
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HMG CoA synthase, HMG CoA lyase
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The primary keto-acid is:
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Acetoacetate
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Acetoacetate is reduced to:
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D3 hydroxybutyrate
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Where is acetoacetate:succinyl CoA transferase present?
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Mitochondria of all tissues except liver
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Thiolase
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cleaves acetoacetyl CoA to yield 2 molecules of acetyl CoA
- low in brain but induced by starvation |
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Ability of mitochondria to use acetyl CoA limited by:
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Accumulation of NADH & ATP
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Acetyl CoA can't be used for fatty acid synthesis in fasting because:
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Acetyl CoA carboxylase inhibited by glucagon and fatty acyl CoA; this in turn forces acetyl CoA into the ketogenic pathway
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What causes acetyl CoA accumulation in type 1 diabetics?
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the enhanced gluconeogenesis depletes OAA and prevents acetyl CoA from re-entering citric acid cycle
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What is typical presentation of fatty acid oxidation disorder?
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infant or young child with lethargy & coma associated with fasting. HYPOKETONIC HYPOGLYCEMIA
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Presentation of CPT-II deficiency:
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Primarily involves muscle
Muscle weakness & exercise intolerance Rhabdomyolysis following periods of intense exercise |
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The presence of what in the urine can help in diagnosis of fatty acid oxidation disorders?
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The degradation products that accumulate in the urine
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What is the most common of the fatty acid oxidation enzyme defects?
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Defect in MCAD (medium chain acyl-CoA dehydrogenase)
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What is mechanism of hypoketonemia in fatty acid oxidation disorders?
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If can't oxidize fatty acids, can't produce precursors needed for ketone body production
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What is reason for hypoglycemia in fatty acid oxidation disorders?
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1. B-oxidation produces good deal of ATP needed for gluconeogenesis
2. body unable to use fatty acids or ketone bodies for energy so uses up a LOT of glucose |
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Why does a defect in one dehydrogenase prevent oxidation of all fatty acids?
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Accumulation of fatty acyl CoA depletes cell of CoA and carnitine
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