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133 Cards in this Set
- Front
- Back
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What is the rate limiting step in the synthesis of fatty acids?
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Acetyl CoA --> Malonyl CoA [EZ: Acetyl CoA Carboxylase]
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Where does fatty acid synthesis take place?
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In the Cytoplasm. Acetyl CoA must leave the mitochondria as citrate and then be reconverted
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What enzyme triggers the release of triglyceride from adipose tissue?
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Hormone sensitive lipase
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What is the rate limiting step in fatty acid oxidation?
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Transport of acyl carnitine into the mitochondria (EZ: carnitine palmitoyl transferase 1, CPT1)
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The acetyl CoA generated by beta oxidation will become a ketone (instead of entering the TCA cycle) only in what conditions?
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Insulin LOW, counter regulatory hormones HIGH, prolonged glucose insufficiency
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How does the body preserve lean body mass in the conditions of starvation?
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Using ketones as an alternative fuel for the brain
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Under what three conditions do ketone bodies form?
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Starvation, diabetic ketoacidosis, alcoholic ketoacidosis
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What is the rate limiting step of ketogenesis?
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Formation of Hydroxyl Methylglutaryl CoA, by HMG CoA synthase
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What processes contribute cytosolic NADPH to fatty acid synthesis?
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Hexose monophosphate shunt and malate to pyruvate conversion
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Why must linoleic and linolenic acid come from the diet?
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Humans lack the ability to introduce double bond and unsaturation at D12
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What tissue contains glycerol kinase, one of the enzymes that makes the glycerol phosphate needed for TAG synthesis?
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Liver only
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What things inhibit enzymatic activity of Acetyl CoA Carboxylase?
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Long chain fatty acids (product of synthetic pathway), phosphorylation of dimers by glucagon induced cAMP dependent kinase
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What things activate Acetyl CoA Carboxylase?
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Citrate (substrate) and dephosphorylation of dimers by insulin induced protein phosphatase (allows polymer to form)
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After the creation on malonyl CoA, what are the steps in fatty acid synthesis (broadly)?
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Oxidation, reduction, dehydration, reduction
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Where does elongation of the LCFA occur after synthesis?
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ER and Mitochondira
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What enzyme is responsible for the energy dependent reaction of activating a Fatty acid (prior to TAG synthesis)?
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Fatty Acyl CoA Synthase
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What must be done in between adding the 2nd and 3rd fatty acids to the glycerol backbone in TAG synthesis?
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Remove the phosphate (phosphatase)
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What are the two ways the body can generate glycerol phosphate for TAG synthesis?
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Glycerol-P dehydrogenase acting on DHAP (glycolysis intermediate) or glycerol kinase activity (only in liver)
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What effect does increased carbohydrate ingestion have on fatty acid synthesis? What about decreased carbs or increased fat?
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increased FA synthesis; decrease
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What are the steps in beta oxidation of fatty acids?
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Oxidation, hydration, oxidation, thiolytic cleavage
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How do fatty acids travel through the plasma?
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albumin-bound
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What happens to the three carbon chain left after oxidation of an odd-numbered LCFA?
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Propionyl CoA [Propionyl CoA Carboxylase] --> D-methylmalonyl CoA [racemase] --> L-methylmalonyl CoA [mutase] --> succinyl CoA
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What additional enzyme is necessary for oxidation of a mono-unsaturated fatty acid? Poly-unsturated?
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3,2-enoyl CoA isomerase for mono; 3,2-enoyl CoA isomerase and NADPH-dependent reductase for poly
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Where does preliminary oxidation of VLCFA (20 or more carbon chain) occur?
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peroxisome
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What deficiency leads to Zellweger's syndrome (aka hepato-renal-cerebellar disorder)?
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Defect in activity of peroxisomal VLCFA oxidation
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What characteristic symptoms arise from a defect in Medium Chain Dehydrogenase?
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hypoglycemia, increase carnitine in urine, decreased carnitine in tissue, low ketones in fasting state
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What intermediate of the fatty acid biosynthetic pathway acts as an inhibitor of CPT1?
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Malonyl CoA
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What is the only tissue in the body with significant levels of HMG CoA synthase?
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Liver
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What enzyme is lacking in the liver, preventing the breakdown of ketone bodies in this tissue?
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thiophorase
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What determines whether peripheral tissues (including brain) will oxidize ketone bodies for energy?
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the concentration of ketone bodies in the blood
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What happens when acetyl CoA levels in liver excede oxidative capacity?
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Ketogenesis
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who cares
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no one
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What are enzymes that metabolize glycerophospholipids?
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Phospholipase A1, A2 (for fatty acid cleavage) C (at the alcohol position) and D (after phosphate)
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Which sphingolipids give us the blood antigen system?
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globosides
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What sphingolipid has a phosphocholine as the head group?
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shingomyelin
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Which phospolipase is important as part of a second messenger cascade? What are the products of this enzyme's activity?
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Phopholipase C (P1,4,5 P2 specific); PI3 causes an increase in Ca++, DAG activates PKC
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What are the two distinct pathways through which glycerophospholipids can be synthesized? Which one makes anionic products?
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Diacylglycerol-CDP (anionic products = PI, PG), vs. diacylglycerol alone
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Which lipiprotein particles contain ApoB48? ApoB100?
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48 on Chylomicrons from the intestine (exogenous fats) 100 on VLDL from liver (endogenous fat transport)
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ApoC2 is transfered onto Chylomicrons and VLDL in the blood from what source?
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HDL
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What does ApoC2 do at the interface of capillaries to peripheral tissue?
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Activates Lipoprotein lipase, allowing TAG transfer and metobolism
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What two physiologic states can induce actvity of Hormone sensitive lipase? By the action of what hormones?
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Fasted state glucagon; strenuous exercise epinephrine
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What apolipoprotein serves as a recognition molecule for liver endocytosis of lipoprotein particles?
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ApoE
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What apoprotein is the structural backbone for HDL particles?
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Apo A1
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When tag levels are high in the blood, what mechanism exists to remove some of the circulating tags?
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HDL can pick up TAG from VLDL in exchange for cholesterol esters (EZ: Cholesterol ester transfer protein CETP)
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The enzyme LCAT transfers a fatty acid from lecithin onto cholesterol, for what purpose?
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Resulting non-polar cholesterol ester is more tightly bound to HDL
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Elevated serum levels of what apolipoprotein are associated with premature coronary heart disease (esp in women)?
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Apo(a)
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What protein is Apo(a) similar in structure to?
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Plasminogen
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For pediatric patients, what are the BMI cutoffs for overweight, obesity and extreme obesity?
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85-95% - overweight, >95% - obese, >99% - extreme
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For a child under 3 years old, what is a better predictor of later obesity than the child's weight?
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Mother's weight
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How do you calculate a patient's BMI
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BMI = wt(kg)/ht(m^2)
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What are the waist circumference values that infer an increased health risk for men and women?
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women > 35, men > 40
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When is waist circumference most valuable in predicting health risk?
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In patients who are overweight or mildly obese (BMI 25-35)
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How is the diagnosis of metabolic syndrome made?
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Pt has 3 or more of following:
Waist circumference (F:>35, M:>40) TG > 150 (or on meds) HDL < 40M, <50F (or on meds) BP either >130/>85 (or on meds) Fasting glucose >100 (or on meds) |
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If the patient already has a comorbid condition, at what BMI should you recommend 1) lifestyle change? 2)drugs? 3)surgery?
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1) BMI 25 2) BMI 27 3) BMI 35
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If your patient has no comorbid conditions, at what BMI should you recommend 1) lifestyle change? 2)drugs? 3)surgery?
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1) BMI 27 2) BMI 30 3) BMI 40
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What is most practical way to put your patient into negative energy balance for weight loss?
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Decrease food intake by 500-1000 kcal (but physical activity is still essential)
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What do most successful diet plans have in common?
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Low fat, frequent weigh-in, eat breakfast, decrease or limit TV time, lots of physical activity
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What are some strategies for decreasing food intake?
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dietary log with calorie budget, 75% portion reduction, meal replacements, commercial programs
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How does physical activity change the results of a weight loss program?
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Maintenance after weight reduction
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How much physical activity does your patient need to do to maintain weight loss?
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60-90 minutes
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How can you use a pedometer to increase your patient's lifestyle activity?
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Get a baseline, increase by 500 steps/day, with continual increases every week
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What are the side effects of statins and how might they manifest?
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Hepatotoxicity (elevated ALT) Myopathy (elevated creatine kinase) Muscle pain
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What is the mechanism of action for resins?
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Bile acid sequestration --> increased LDL uptake for conversion to bile acids
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What is the LDL reduction seen with plant sterols?
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10-15%
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What are the side effects of fibrates?
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skin rash, myopathy, liver function test abnormalities, gi upset.
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When is Ezetimibe contraindicated?
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liver disease, pregnancy, nursing
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What are the signs and symptoms of severly elevated triglycerides?
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pancreatitis, lipemic retinalis, eruptive xanthoma, hepatosplenomegaly
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What lab values might be seen in a patient with Familial Combined Hyperlipidemia?
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Elevated LDL and/or TG
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What are the risks factors that are used to determine a patients optimal lipid goals?
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CHD risks: age, family history of premature CHD, smoking, Hypertension, low HDL
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If your patient has coronary heart disease or a risk equivalent, what should be their LDL goal?
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<100, <70 optional
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What is the optimal lipid goal for a patient with 2 or more risk factors?
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LDL < 130 (100 optional)
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What side effect of nicain makes it hard for patients to continue using?
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Flushing
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What genetic mutation leads to Familial Hypercholesterolemia?
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LDL receptor
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In what lipid disorder might you see LDL levels 2-4 times normal and tendinous xanthomas?
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Familial Hypercholesterolemia
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What is primary target of therapy in a patient with low HDL?
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reducing LDL
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What is the key regulated step in protein catabolism?
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production of carbamoyl phosphate by carbamoyl phosphate synthase I
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What amino acids are ketogenic?
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Leucine and Lysine
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Which amino acids can be either glucogenic or ketogenic?
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Phenylalanine, Isoleucine, Tryptophan, Tyrosine
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What modified amino acids are combined to form Collagen?
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hydroxyproline and hydroxylysine
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What cofactor is absent in the development of scurvy?
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Lack of Vit C --> weakened collagen
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What cofactor is required for the production of gamma-carboxy-glutamate (Gla)?
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Vit K
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What important biomolecule used a gamma-carboxyglutamate residue to target membranes?
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Prothrombin
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What are the two processes of cellular protein degradation?
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ubiquination and lysosomal degradation
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What happens to a protein after it has been ubiquinated?
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it's targeted to the proteasome
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Transamination requires what cofactor?
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PLP, form of B6
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What determines the direction of a reaction catalyzed by aminotransferases?
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concentration of substrate and product
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What is the purpose of a transamination reaction?
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to move an amino group between an amino acid carbon chain and an alpha-ketoglutarate
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What sulfur containing amino acid is an essential dietary amino acid?
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methionine
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What amino acid is synthesized from methionine, and becomes essential if cannot be synthesized?
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Cystine
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What important function is served by cystine?
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forms disulfide bridges, which stabilize protiens in conformation
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SAM is involved in the methylation of what important biomolecules?
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Norepinephrine --> epi; methylation of DNA at cytosine
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What molecules can be synthesized from the homocysteine made from SAM?
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methionine, cysteine, succinyl CoA, glutathione
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What cofactors are needed to re-synthesize methionine from homocysteine?
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B12 and Folate
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What are the symptoms of elevated homocysteine of non-genetic cause?
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vascular disease, impaired wound healing
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What is the symptom and recommended treatment of cysteinuria?
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kidney stones due to cysteine crystals, treat with penicillamine (makes cysteine more soluble
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What cofactor is required to make cysteine (and alpha-ketoglutarate) from homocysteine?
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PLP needed in two subsequent reactions
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What does Glutathione do?
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returns methemoglobin to hemoglobin, protects against racidal oxygen species, keeps enzymes in reduced state (regulating activity)
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What enzymes protect against radical oxygen?
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Superoxide dismutase, catalase, Glutathione peroxidase
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What two molecules can be used to catalyze 1-carbon transfer?
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SAM and tetrahydrofolate
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What drug blocks the synthesis of tetrahydrofolate and in what conditions is this useful?
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methotrexate (blocks enzyme activity of dihydrofolate reductase) targets rapidly dividing cells
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What are the regulated enzymes for protein catabolism?
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ALT and AST aminotransferases, carbamoyl phosphate synthase I, Glutamate dehydrogenase
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What does ALT do?
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Converts alanine and a-ketoglutarate to pyruvate and glutamate (and back)
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What does AST do?
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Glutamate and OAA --> aspartate and a-ketoglutarate (and back)
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What determines the direction of the ALT and AST transamination reactions?
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Concentration of substrates, because Keq ~ 1
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What kick starts the urea cycle by activating carbamoyl phosphate synthase I?
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N-acetylglutamate
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Where do the two amine groups come from in the urea cycle?
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Carbamoyl Phosphate and aspartate (AST product)
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What are the activators of glutamate dehydrogenase? Inhibitors?
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ADP and GDP; ATP and GTP
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What does glutamate dehydrogenase do?
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Glutamate --> NH4+ and a-ketoglutamate
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What two regulation points of protein catabolism happen at the level of glutamate dehydrogenase?
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Concentration of glutamate drives reaction, ADP and GDP activate, ATP and GTP inhibit
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What amino acid transports ammonia in the blood to prevent toxicity?
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Glutamate
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What important molecules are made from arginine?
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NO (NT), creatine phosphate (energy in muscle), and ornithine (urea cycle)
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What are the essential amino acids?
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Methionine
Threonine Valine Phenylalanine Isoleucine Tryptophan |
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What glucogenic amino acid is synthesized from aspartate and asparagine?
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OAA
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What genetic defect results in maple syrup urine disease?
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defect in Branched chain a-keto acid dehydrogenase
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What must happen to branched amino acids before they can be metabolized?
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must be decarboxylated
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Decarboxylation of the branched amino acids leads to what compounds?
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succinyl CoA and Acetyl CoA
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What neurotransmitters are derived from Tyrosine?
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Dopamine, NE, EPI
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What reactions use BH4 as a cofactor?
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Phe --> Tyr, Tyr --> Dopa, Trp --> 5-HT
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What molecules are derived from tryptophan?
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melatonin, 5-HT, niacin
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What are the symptoms of untreated Phenylketonuria?
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seizures, mental retardation, spasticity, odor (phenylacetate) (in adults, irritability and MRI changes)
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What treatments are recommended for someone with classic PKU?
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diet limiting Phe to only amt needed for growth, can also try large neutral a.a. to compete with phe for brain uptake, BH4 supplementation
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What are the symptoms of homocystinuria?
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thromboembolic events, seizures, mental retardation, lens dislocation, marfanoid habitus, psych disturbance, osteoporosis
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Why might a homocystinuria defect not present at birth?
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if pt responsive to B6, levels of methionine will not be significantly elevated
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What are the key differences between purine and pyrimidine synthesis?
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Purines made on the sugar, Initial product purine=IMP, pyrimidine=UMP, conversion of one base to another in purines as monophosphate, in pyrimidines as triphosphate
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What is most common deficiency of the urea cycle?
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OCT
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What is the normal function of OCT?
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Transfer the carbamoyl-phosphate into the urea cycle
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Where do the atoms come from to make a pyrimidine base?
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Aspartate, NH3 (cytosolic, not ureic), CO2
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What deficiency results in succinylpurinemic autism?
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adenylosuccinate lyase deficiency, turns CMP into AMP
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Where do the atoms come from to make a purine base?
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Glutamine, glycine, Aspartate, 2 formate, CO2
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How is ribonucleotide reductase regulated?
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it's on/off activity regulated at primary site (ATP on/dATp off), secondary regulation determines subsequent substrate
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What is the salvage pathway for nucleotide synthesis?
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Attach a premade base to PRPP via transferase enzyme
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What enzyme may be deficient in patients with Lesch-Nyhan disease?
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HGPRT - transfers either hypoxanthine or guanine onto PRPP
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What are the clinical features of mild Zinc deficiency?
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growth retardation and anorexia
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