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What is considered as the sum of protein synthesis + protein degradation?
Protein turnover
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Amino acids released by protein break-down that can be utilized for protein synthesis efficiently refers to what process?
Nitrogen recycling
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Which proteins are specifically targeted for degradation since their turnover is high? What is a result of this feature?
- Proteins with very short half-lives.
- They respond quickly to acute changes in protein intake.
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What are the two products of protein oxidation/excretion?
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How is the rate of protein turnover assessed non-invasively?
With non-radioactive table isotopes (measured in urine).
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What is mathematically equivalent to the difference between total protein synthesis minus total protein breakdown?
Nitrogen balance
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Do catabolic disorders result in increased or decreased protein breakdown?
Increased
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Protein feeding for someone with a catabolic disorder results in...?
A relative increase in protein synthesis which minimizes N losses.
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Protein restriction for someone with a catabolic disorder results in...?
- Adaptation of protein metabolism (decreased protein turnover/degradation).
- Amino acid oxidation.
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What are the endogenous factors that affect protein turnover?
- Age/aging
- Growth
- Body composition (fat free mass, adipose)
- Various diseases (catabolic, hypermetabolic)
- Example: rate of protein turnover tends to decrease with age in humans.
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What are the exogenous factors that affect protein turnover?
- Nutritional status (protein and energy)
- Anabolic substances
- Prolonged exercise
- Recovery from malnutrition ("regrowth" in adults)
- Example: during endurance exercise, protein utilization as a fuel increases and the net amount of whole body protein is depressed.
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A drop in total energy intake while keeping protein intake constant, as seen in a weight-loss diet, would cause what kind of effect?
Increase in protein needs due to an increase in body protein loss (enhanced protein oxidation).
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What are the metabolic processes that require energy?
- Protein synthesis/degradation in particular, activation of AAs and formation of peptide bonds during elongation of peptides.
- r-RNA and t-RNA turnover
- AA transport
- Ion pumps and channels
- Signal transduction and protein translocation.
- Glucose-alanine cycle
- Urea synthesis
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What is the total energy requirement for protein synthesis and protein turnover in adults and premature babies?
- 20% of resting energy expenditure (adults)
- 30% of resting energy expenditure (premature babies)
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What are the major metabolic fates of amino acids in the amino acid pool?
- Synthesis of new endogenous proteins/other biological substances.
- Oxidized, yielding urea, ammonia, and CO2 as terminal end-products (ureagenesis).
- Converted into other compounds (gluconeogenesis).
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What are the factors that regulate catabolism of amino acids?
Mainly regulated (short term) by substrate availability from exogenous supply (food) or endogenous mobilization in the post-absorptive state (protein breakdown).
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Are surplus amounts of amino acids stored?
No. Excess AAs are used as metabolic fuel and oxidized.
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Where does the process of the urea cycle mainly occur in terrestrial vertebrates?
The liver
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What is the biochemical role of the urea cycle in humans?
Sole mechanism for ammonia disposal.
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What are the biochemical properties of urea?
- Water soluble "waste" end product of protein metabolism.
- Produced by the liver, excreted by kidneys in urine.
- Safe vehicle to transport and excrete excess nitrogen.
- Is the main nitrogen-containing substance in human urine.
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What is the urea salvage pathway and what is its purpose?
- Microflora (bacteria) in the lower hind gut (colon) recycle urea by way of hydrolysis, allowing some nitrogen to be recovered.
- This nitrogen returns to the AA pool and is retransformed into AAs in the liver.
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What are factors that stimulate and inhibit gluconeogenesis?
- Stimulate: fasting diet and low carbohydrate diet (<100 g/day).
- Inhibit: high carbohydrate diets.
- Basically it is influenced by the nature and level of dietary intakes.
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Is gluconeogenesis simply a reversal of the glycolytic pathway? Why/why not?
- No
- The irreversible steps of glycolysis are bypassed during gluconeogenesis.
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What term is used to describe the simultaneous activation of glycolysis and gluconeogenesis? Why is it called this?
- Futile cycle
- Both processes activated at once would result in a waste of energy, therefore they are tightly regulated to prevent simultaneous activation.
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Although glycolysis occurs universally throughout the body, gluconeogenesis occurs in specific locations. What are they?
Liver and kidneys
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What is the key hormone that regulates the metabolic transformation of amino acids into glucose in the liver and kidneys?
Glucagon
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What are the roles of glucagon?
- Stimulates gluconeogenesis (inhibits glycolysis).
- Enhances glycogen breakdown (inhibits glycogen synthesis).
- Allows release of free glucose into circulation to maintain glycemia.
- Stimulates hepatic ureagenesis (hypergluconemia).
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What are the hormones that regulate gluconeogenesis?
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What are the precursors for gluconeogenesis in muscle and fat?
- Lactate (muscle)
- Glycerol (fat)
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What are two patient populations that have high protein demands and turnover rates?
- Premature babies
- Children recovering from malnutrition
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What are the sources of amino acids for the amino acid pool?
- Exogenous proteins (digestion, absorption).
- Tissue protein breakdown during protein turnover.
- De novo synthesis, including AAs (and ammonia) from urea salvage.
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How are excess amino acids disposed of?
- Increased oxidation
- Enhanced ureagenesis
- Gluconeogenesis
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What are the types of glycosidic linkages present in the glycogen structure?
- α-1,4 glycosidic linkages (between glucose residues)
- α-1,6 glycosidic linkages (branchpoints)
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What are the types of chains present in the glycogen structure?
- Inner B-chains (2 branchpoints)
- Outer A-chains (unbranched)
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What is the general structure of glycogen?
- 12 tiers of chains w/ ˜55000 glucose residues
- Molecular mass of ˜107 kDa
- Diameter of ˜44nm
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What other types of molecules are present in glycogen besides glucose residues?
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What enzyme is responsible for the addition of other molecules to the glycogen structure?
Glycogen synthase
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What are the effects of excessive phosphorylation of glycogen?
- Lafora disease (epilepsy)
- Multiple cycles of expansion and contraction cause chemical/metabolic insults that can accumulate, and results in aberrant structures that sometimes escape normal metabolism and degenerate into an insoluble deposit.
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What are the locations of glycogen storage?
- Skeletal muscle and liver (major deposit)
- Other organs capable of glycogen synthesis are the kidney, heart, adipose, and brain.
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What are the precursors and donors used in glycogen synthesis?
- Precursor: Glucose (carbohydrate)
- Precursor: Lactate or alanine (gluconeogenic)
- Donor: Activated NDP-sugar UDP-glucose
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What are the types of glucose transporters used in the direct pathway?
- GLUT1 (widely distributed, basal glucose transport)
- GLUT2 (prominent in liver and β-cells of pancreas, admits glucose based on positive glucose gradient between blood and tissue)
- GLUT4 (up-regulated by insulin, important in insulin sensitive tissues like skeletal muscle and adipose)
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How are the UDP-glucose, glycogenin primer and glycogen A&B chains synthesized?
- UTP is converted to UDP by UDP-glucose pyrophosphorylase.
- Glycogenin self-glucosylates to form oligosaccharide primer.
- Glycogenin interacts with glycogen synthase which forms the majority of the α-1,4 glycosidic linkages.
- α-1,6 glycosidic branchpoints are formed by branching enzyme.
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What is the difference between the indirect and direct pathways for glycogen synthesis?
- Indirect pathway=glyconeogenesis that occurs with gluconeogenic precursors (lactate, alanine, etc)
- Direct pathway=requires transport of glucose into cells with GLUTs
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What are the products of glycogen degradation?
- Glucose-1-phosphate (from α-1,4 linkages)
- Free glucose (from α-1,6 linkages)
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What are the conditions that stimulate glycogen breakdown?
- Nutritional deprivation (hepatic glycogenolysis)
- Exercise (muscle glycogenolysis under conditions of increased cAMP and Ca2+)
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How is the breakdown of glycogen mediated in the first pathway?
- Actions of glycogen phophorylase.
- Actions of debranching enzyme AGL.
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How is the breakdown of glycogen mediated in the second pathway?
Glycogen is transferred to the lysosome and hydrolyzed to glucose by lysosomal α-glucosidase.
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What is the biochemical function of glycogenin?
- 1. Transfers glucose from UDP-glucose to a tyrosine residue within the protein itself.
- 2. From there it forms α-1,4 glycosidic linkages until the oligosaccharide chain is 10-20 residues long.
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What are the genes that encode glycogenin and how are they expressed?
- GYG1: widely expressed
- GYG2: expressed in liver, heart, pancreas
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What type of gene mutation can cause glycogenin to be defective? What effect does this have on the patient?
- Nonsense mutation in one allele and missense mutation (T83M) in the other which leads to inactive glycogenin-1.
- Patient has muscle weakness and cardiac abnormalities following exercise.
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What is the biochemical function of glycogen synthase?
It is responsible for the bulk synthesis of glycogen by formation of the α-1,4 linkages with UDP-glucose as the glucosyl donor.
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What are the genes that encode glycogen synthase in mammals and how are they expressed?
- GYS1: expressed in skeletal muscle and most other cells capable of glycogen synthesis
- GYS2: expression restricted to liver
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How is glycogen synthase regulated?
- Phosphorylation
- Allosteric activation by glucose-6-phosphate
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What are the types of glycogen synthase mutations, and what are they physiological effects on patients?
- Mutation of GYS2 (GSD 0): causes hepatic glycogen deficiency. Patients have mild symptoms, postprandial hyperglycemia, and fasting hypoglycemia. Hepatic glycogen synthase activity is reduced.
- Mutation of GYS1: glycogen synthase and glycogen are absent from muscle. Causes cardiac problems, and poor exercise performance. Occurs as a result of a homozygous mutation of R462X in GYS1.
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What are the enzymes involved in the rate-determining steps of glycogen synthesis in muscle?
- GLUT4
- Hexokinase
- Glycogen synthase
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Name the general location of glycogen storage inside cells.
Cytosol
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What is glycogen autophagy?
- Autophagy is comprised of processes described as a mechanism for random recycling of cellular materials under conditions of nutritional deprivation.
- The term glycogen autophagy has been applied particularly to the liver of newborns.
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What is the location of glycogen in liver and muscle cells?
Close to membranes, endoplasmic reticulum (liver), sarcoplasmic reticulum (muscle).
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What are the causes and physiological effects of Lafora Disease?
- 'Lafora bodies' are deposits containing poorly branched, insoluble glycogen-like carbohydrate (polyglucosan) in individuals with an autosomal recessive neurodegenerative disorder called Lafora Disease.
- Causes progressive myoclonus epilepsy, dementia and death (within 10 years of symptoms starting).
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Where are Lafora bodies found in humans?
- Brain (neurons)
- Skeletal muscle
- Heart
- Liver
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Name the location of and substrates for laforin.
- Skeletal muscle
- Liver
- Kidney
- Heart
- Brain
- Tissues
- Substrates: Lafora bodies
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What are the substrates for malin?
Debranching enzyme AGL
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