Section IV Part 1 (Chapters 19-20, 22-23) Flashcards
What is metabolic homeostasis?
The control of the supply and demand of carb, fat or protein, from which ATP is derived
How is homeostasis regulated?
Concentration of metabolites in blood (too much = Store it; too little = Use/Breakdown)
Hormonal control - (Insulin vs Glucagon/Epinephrine/Cortisol)
CNS direct tissue metabolism directly or via hormones
How does insulin maintain homeostasis & regulate fuel mobilization & storage?
Anabolic hormone that promotes storage & growth when blood glucose is high
Made by beta cells of the pancreas
How does glucagon maintain homeostasis & regulate fuel mobilization & storage?
A counterregulatory hormone of insulin
Fuel mobilization hormone
Promotes release/use/breakdown of fuel stores during fasting/stressful states
Through the liver (glycogenolysis/gluconeogenesis) & adipose tissue (fatty acid release)
Made by alpha cells of the pancreas
How does epinephrine & cortisol work in terms of fuel mobilization
From the CNS, epinephrine & cortisol are insulin counterregulatory hormones, released due to stress/exercise/hypoglycemia
Increase the availability of fuel
Insulin stimulates
-> Glucose storage as glycogen
-> Stimulates fatty acid synthesis & storage
-> Stimulates amino acid uptake & protein synthesis
Glucagon activates
Gluconeogenesis & glycogenesis
Fatty acid release from adipose tissue
Epinephrine stimulates…
Stimulates glucose production from glycogen (muscle & liver)
Stimulates fatty acid release from adipose
Cortisol stimulates…
Stimulates amino acid mobilization from muscle protein
Stimulates gluconeogenesis in order to produce glucose for liver glycogen synthesis
Stimulates fatty acid release from adipose tissue
How is insulin produced?
A peptide hormone synthesized by BETA-cells from the iL of the pancreas; initially a preprohormone, converted to proinsulin in rough ER (via cleaved N-terminal) and folded with cystine disulfide bonds, then transported to Golgi to become active insulin that coprecipitates with Zn in vesicles
Why is C-peptide clinically significant?
Proteases remove the C-peptide, which decreases the solubility
How is glucagon produced?
A peptide hormone made by ALPHA-cells of iL of the pancreas; First, preproglucagon, converted to proglucagon in RER and later cleaved to mature glucagon
What is the physiological mechanism of insulin secretion by the pancreatic islets cells?
Abundant glucose enter BETA-cell via GLUT2 and is oxidized to g6p then into glycolysis, TCA, and oxidative phosphorylation creating ATP; the rise in ATP in BETA-cell closes K+ channels (= depolarize PM) and activates Ca2+ channels, leading to Ca2+ influx and vesicular release of INSULIN
What are the regulators of insulin?
Major -> glucose
Minor -> amino acids, neural input, gut hormones, epinephrine (adrenergic)
What are the regulators of glucagon?
Major -> glucose, insulin, amino acids
Minor -> cortisol, neural, epinephrine
What regulator of insulin gives a negative effect (only one)?
Epinephrine
What regulator of glucagon gives a negative effect (only two)?
Glucose & insulin
Cell signaling of insulin
Insulin bind to plasma membrane receptor with tyrosine kinase activity = phosphorylation of enzymes = IRS binds to proteins = different tissue-response: reverse glucagon effect, more phosphorylation cascade; growth/ protein synthesis; induce/repress enzymes; AND glucose/AA transport into cells
Cell signaling of glucagon
Glucagon bind G-protein receptor which is coupled to adenylate cyclase = cAMP production = activate PKA = phosphorylation of S-residues: glycogen degradation, inhibit glycogen synthesis and glycolysis in liver, kidney, but NOT skeletal muscle (lack glucagon receptor)
Cell signaling of epinephrine
EPI is similar to glucagon, though bind to adrenergic receptors = activate G protein = cAMP production & PKA or PIP2 system; WILL affect skeletal muscle
Cell signaling of cortisol
Cortisol is a steroid hormone = traverse plasma membrane; bind intracellular receptors; form complex; enters nucleus and directly interact with DNA to alter gene transcription: induce gluconeogenesis to blood glucose levels
Molecular pathology of maturity-onset diabetes of the young (MODY)
Mutated pancreatic glucokinase (ATP); dampen insulin release, need to be at higher blood glucose concentration for insulin to be released at baseline
Type I diabetes mellitus pathology
Autoimmune attack of BETA-cells = no insulin production = treated by insulin injections
Type II diabetes mellitus pathology
Insulin resistance via non-responsive receptors (receptor number and affinity are still normal) = treated by diet changes and watching sugar intake
Insulinoma pathology
BETA-cell tumor that hypersecretes insulin = causes low blood glucose
Neonatal diabetes
One cause of neonatal diabetes is a mutation in a subunit of the K+ channel in various tissues. Such a mutation in the pancreas leads to permanent opening of the K+ channel, keeping intracellular Ca2+ levels lows, and difficulty in releasing insulin from the beta-cells
What is delta G?
Defined as the quantity of free energy that can be used to work; energy level between product and substrate of a rxn; depends on temperature, pH and pressure
Negative delta G means…
Exergonic/spontaneous
Positive delta G means…
Endergonic/nonspontaneous
Delta G energy production must be … than delta G energy use in order for cells to …
Higher, live
What is the role of ATP as an energy currency?
ATP is the energy currency of life
What is the operation of the ATP/ADP cycle?
Oxidation produces ATP that can be hydrolyzed to ADP and provide energy to perform work
Hydrolysis of ATP to ADP releases energy because ADP and phosphate are more stable with lower bond energy
Usually regulated by phosphoryl transfer reactions, not directly hydrolysis
What is the structure/property/function of ATP
Phosphoanhydride bonds/unstable bonds between the phosphate groups of ATP (due to repelling negative charges) can be hydrolyzed to form more stable substrates (ADP and inorganic phosphate); this is a favorable rxn that releases energy as heat
What does a high-energy bond mean?
Any bond that releases as much energy as the ATP
What are the high energy bonds in molecules other than ATP?
UTP (combine sugars), GTP (proteins) and CTP (lipid) are equal to ATP in energy
What is mechanical work?
the conversion of chemical bond energy to physical movement via conformation change of protein, an example is muscle contraction; ATP hydrolysis while bound to myosin ATPase changes the conformation of myosin
What is biochemical work?
Transfers energy from the cleavage of ATP to power the rxns that require energy such as anabolic/biosynthetic pathways; DNA synthesis, glycogen synthesis, ammonia conversion to urea)
What is the daily ATP consumption of the heart?
16
What is the daily ATP consumption of the brain?
6
What is the daily ATP consumption of the kidneys?
24
What is the daily ATP consumption of the liver?
6
What is the daily ATP consumption of the skeletal muscle at rest?
.3
What is the daily ATP consumption of the skeletal muscle (while running)?
23.6
What is greater than muscle when exercising in terms of ATP consumption?
Kidneys
What is reduction potential?
Energy change when a compound accepts an electron (e-) or becomes reduced; the more negative the potential = greater energy for ATP generation available when e- is passed on to oxygen
Explain the role of oxidation-reduction reactions and the function of electron-carrying coenzymes in energy transfer
Respiration transfer energy from the oxidation of fuel to reduced e-acceptors such as NAD+ and FAD+, which later transfer the high energy e- to O2 in the ETC and form an electrochemical gradient across the inner mitochondrial membrane; this gradient fuels the generation of ATP from ADP
Delta G & Delta G Prime values are…
Additive
ΔG (and ΔGo´) values are additive and can be coupled together to drive thermodynamically unfavorable reactions forward
In a sequence of rxns; some will be exergonic (which can fuel other rxns), others endergonic but OVERALL (DELTA-G is negative) the pathway is favorable
A food molecule’s oxidation state is related to caloric value of food how?
Fat is the most reduced and can be more oxidized, so it yields the most energy (9kcal/g); protein and carbs are partially oxidized and yield less energy (4kcal/g)
CH and CC bonds
Only able to utilize molecules if we have the enzymes to oxidize them as fuel
What sequence of events lead to cell necrosis as a consequence of hypoxia?
Hypoxia leads to physical and transcriptional changes; lack of O2 = lack of ATP generation = no energy for transport of Na+/Ca2+ = death cascade:
impaired Na+ gradient can cause drop in intracellular pH (Na+/H+ exchanger disabled)
Increased intracellular ions = H2O enter cell = hydropic swelling
Swelling trigger release of CK-MB and troponin (detectable)
High Ca2+ triggers cell death via activation of phospholipase that increase plasma membrane permeability and breakdown mitochondria
What increases in hypoxia?
Hypoxia induces transcription factors (HIF) production that increases RBC production to attempt to survive hypoxia
Obesity pathology
Understanding daily caloric needs can enable one to gain or lose weight through alterations in exercise and eating habits
Hyperthyroidism pathology
Thyroid hormone is important in regulating energy metabolism; excessive T3 and T4 release enhances metabolism, leading to weight loss and a greater rate of heat production
Heart attack (myocardial infarction)
The heart requires a constant level of energy, derived primarily from lactate, glucose, and fatty acids. This is necessary so that the rate of contraction can remain constant or increase during appropriate periods. Interference of oxygen flow to certain areas of the heart will reduce energy generation, leading to a MI
Where does glycolysis occur?
Cytoplasm of ALL cells & generates ATP in the presence and absence of O2
What is the overall equation of glycolysis?
Glucose + 2 NAD+ + 2Pi + 2 ADP → 2 pyruvate + 2 NADH + 4 H+ + 2 ATP + 2 H2O
What starts off during glycolysis?
Glycolysis begins with glucose which is oxidized into 2 PYRUVATES, 2 NADH and a net generation of 2 ATP molecules via substrate-level phosphorylation
What steps use ATP in glycolysis?
Phase I/Preparative phase uses 2 ATP: via step (1) Hexokinase and (3) phosphofructokinase-1
What steps make ATP in glycolysis?
Phase II/ATP-generating step makes 4 ATP: via (7) phosphoglycerate kinase and (9) pyruvate kinase
What is substrate-level phosphorylation?
The transfer of phosphate from a high-energy intermediate to ADP = forming ATP
What steps in glycolysis produce NADH?
The oxidation of two glyceraldehyde 3-phosphate generates 2 NADH
What can NADH not do?
Cytosolic NADH cannot cross inner membrane so its equivalents are transferred to ETC by malate-aspartate shuttle or glycerol 3-phosphate shuttle
How does dietary fructose enter the glycolytic pathway?
Fructose enters cells via facilitated diffusion on GLUT5 transporter and is immediately phosphorylated by FRUCTOKINASE into F1P
F1P is cleaved by aldolase B to DHAP and glyceraldehyde
Glyceraldehyde is phosphorylated by triose kinase into G3P;
DHAP and G3P enter the glycolytic pathway
What is aldolase B defect?
Accumulation of F1P in liver and kidney = inhibits glycogenolysis and gluconeogenesis = lactic acidosis and depleted phosphate pool
What is a fructokinase deficiency?
Accumulation of fructose that can appear asymptomatic
What is a polyol pathway?
Polyol pathway (in seminal vesicles) synthesizes fructose from glucose via reduction of glucose by aldose reductase into sugar alcohol SORBITOL, which is oxidized to fructose, used by spermatozoa in female reproductive tract
How does the polyol pathway contribute to the formation of cataracts?
Elevated glucose/galactose can be converted into sugar alcohols by aldose reductase; accumulation of sugar alcohol in the lens due to hyperglycemia/diabetes+ glycosylation of lens = cataract
Classical galatosemia
Deficient galactose-1-P uridylyltransferase = accumulation of galactose 1-P in tissue and galactose in blood and urine = inhibit hepatic glycogen metabolism & UDP sugar pathways; galactose in blood is converted to galactitol; irreversible intellectual disability, cataracts
Nonclassical galactosemia
Deficient galactokinase (first step) = galactosuria but NO galactose-1-P formation = cataract
What are the different fates of pyruvate & NADH under anaerobic conditions?
Anaerobic = re-oxidized by LDH in cytosol & reduction of pyruvate to lactate (fermentation)
What are the different fate of pyruvate & NADH under aerobic conditions?
Aerobic = shuttle reducing equivalent to ETC and oxygen; pyruvate is oxidized to acetyl-coA and enter TCA for complete oxidation or used for fatty acid synthesis if enough ATP
What must be reoxidized in glycolysis?
NADH
Why is glucose metabolism different in various tissues and why are certain tissues are especially or entirely dependent on anaerobic glycolysis?
Tissues that rely on anaerobic glycolysis for ATP have low demand, glycolytic enzymes, few capillaries (large tumors) or lack mitochondria (RBC).
The eye must transmit light and cannot be filled with mitochondria
What is the Cori cycle?
The cycle of lactate and glucose between peripheral tissues and liver
What is the utility of the Cori cycle?
Lactate absorbed and oxidized back to pyruvate to be used for gluconeogenesis in liver, or oxidation for energy in muscle
Biosynthetic functions of the glycolytic pathway
Glycolysis generates ATP and provides precursors for biosynthesis:
-ribose-5-phosphate to the pentose phosphate pathway
- UDP-glucose
-Mannose
-Sialic acid
- 3-phosphoglycerate to SERINE
- pyruvate to ALANINE
- DHAP to TAG backbone
- 2,3-BPG = allosteric inhibitor of O2 binding to heme & coenzyme for phophoglyceromutase
How is hexokinase inhibited?
Hexokinase is INHIBITED by its product = Glucose-6-phosphate (feedback), glucose in a cell must be taken up by pathway as G6P and entered into glycolysis or glycogen synthesis
How is PFK-1 inhibited?
PFK-1 (rate limiting enzyme) is INHIBITED by ATP (allosteric inhibitor) and citrate (plenty of energy
Upregulated by AMP and F-2,6-bisP (need energy)
How is pyruvate kinase inhibited?
Pyruvate kinase is INHIBITED by ATP
Upregulated by F-1,6-bisP
How is PDH inhibited?
PDH is INHIBITED by NADH and acetyl-coA
Upregulated by ADP and Ca2+
What is the TCA cycle?
takes in acetyl-CoA (2C) from a variety of sources and combines it with oxaloacetate (4C) to form citrate (6C) which rearranges to isocitrate and undergoes oxidative decarboxylation (generating 2 NADH / 2 CO2/ GTP) to form succinate (4C) which oxidizes back to oxaloacetate (4C) with generation of FAD2H and NADH
What is produced in the TCA cycle?
2 CO2, 3 NADH, 1 FADH2, 1 GTP
Where does the TCA cycle take place?
In the mitochondria & requires A LOT of vitamins/minerals
What vitamins/minerals are required in TCA cycle?
Niacin/NAD+, riboflavin/FAD/FMN, pantothenic acid/coenzyme A, thiamin, Mg2+, Ca2+, Fe2+ and phosphate
CoA from acetyl is a coenzyme for
Citrate synthase
NAD+ acts as a coenzyme for
Isocitrate DH & malate DH
FAD acts as a coenzyme for
succinate DH
What does alpha-ketoglutarate DH use as coenzymes
TPP, lipoate, and FAD
FAD & NAD+ are… coenzymes
E-accepting
CoA(SH) forms…
A high energy thioester bond that can be cleaved and fuel TCA cycle (substrate phosphorylation of GTP)
TPP from thiamine cleaves what bond next to a keto group
C-C bonds
Lipoate has a functional end…
That accepts e- and transfer it to CoASH
What is the overall ATP production in the TCA cycle per one acetyl-CoA?
10 ATP
What are the reactions involved in energy production?
The conversion of isocitrate to ALPHA-ketoglutarate by isocitrate dehydrogenase generates a CO2 and NADH
The oxidative decarboxylation of ALPHA-ketoglutarate to succinyl-CoA is accomplished by ALPHA-ketoglutarate dehydrogenase complex; generating another CO2 and NADH
Succinyl-CoA thioester bond is catalyzed by succinate thiokinase to make a GTP from GDP and Pi (substrate-level phosphorylation) and succinate
Oxidation of succinate to fumarate by succinate dehydrogenase transfers e- to an FAD to generate FADH2 (fumarate -> malate)
Malate is oxidized by malate dehydrogenase and donates e- to NAD (forming NADH) to oxaloacetate
The overall yield of TCA cycle
3 NADH (2.5 ATP), 1 FADH2 (1.5 ATP) and 1 GTP (1ATP) = 3(2.5) + 1.5 + 1= 10 ATP
Citrate synthase regulation of TCA cycle
+ by OA; - by citrate
Isocitrate dehydrogenase regulation of TCA cycle
(+) by ADP and Ca2+; (-) by NADH
Alpha-ketoglutarate dehydrogenase
(+) by Ca2+; (-) by NADH/succinyl-CoA/GTP
What is inhibited by NASH & acetyl-coA
PDH
What is PDH upregulated by?
ADP + Ca2+
What are the sources of acetyl coA for the TCA cycle?
- Beta-oxidation of FA (palmitate)
- Degradation of ketone bodies (Beta-hydroxybutyrate & acetoacetate)
- EtOH oxidation (acetate)
- Glucose/Alanine/Serine -> Pyruvate
- Leucine/Isoleucine oxidation
How is acetyl CoA synthesized from pyruvate by the pyruvate dehydrogenase complex?
PDC oxidizes pyruvate to acetyl-CoA via 3 catalytic subunits: pyruvate decarboxylase + TPP (E1); transacetylase + lipoate (E2); dihydrolipoyl dehydrogenase + FAD (E3)
How is the pyruvate dehydrogenase complex regulated?
PDC regulation:
(+) by PD phosphatase & Ca2+ & insulin
(-) by PD kinase (inhibited by ADP/ pyruvate), acetyl-CoA and NADH
TCA intermediates: citrate efflux
Allows for cytosolic FA synthesis
TCA intermediates: malate
Allows for cytosolic gluconeogenesis
TCA intermediates: succinyl CoA
Allows for heme synthesis
TCA intermediate: alpha-ketoglutarate in brain
Allows for glutamate to GABA = neurotransmitter synthesis
TCA intermediate- alpha-ketoglutarate in muscle
Goes to glutamine -> amino acid synthesis
What is the purpose of anaplerotic reactions?
Anaplerotic rxn replenish the intermediates of the TCA cycle in order to keep the carbons present that regenerate oxaloacetate:
- Liver/Kidney, pyruvate carboxylase: biotin forms covalent intermediate with CO2 which activates it + pyruvate = oxaloacetate
- AA oxidation:
A & S enter via pyruvate carboxylase = oxaloacetate
I & V become succinyl-CoA in tissue with mitochondria (except liver
M, T, fatty acids become succinyl-CoA in liver
Q/E becomes ALPHA-ketoglutarate
What is the consequence of pyruvate carboxylase deficiency (Leigh disease)
Pyruvate carboxylase deficiency leads to pyruvate accumulation which is converted to lactate = lactic academia;
-> pts will have severe intellectual disabilities via loss of cerebral neurons;
-> in the brain TCA intermediates make glutamine = essential for neuronal survival
What will be the effects of a thiamine deficiency on the synthesis of acetyl CoA & the TCA cycle?
Thiamin is a precursor to the coenzyme TPP for both pyruvate dehydrogenase complex and ALPHA-ketoglutarate dehydrogenase; thus a deficiency of thiamin would result in low concentration of acetyl-CoA and faulty TCA cycle in cells that have a high demand of ATP, like the HEART (beriberi)
Thiamin deficiency leads to an accumulation of ALPHA-ketoglutarate, pyruvate and other ALPHA-ketoacids in the blood
How does chronic alcoholism cause thiamine deficiency? What does it impact?
Alcohol inhibits the active absorption of thiamin = thiamin deficiency, which presents as cardiomyopathy = high-output heart failure or wet beriberi due to dilated peripheral vasculture/fluid retention affecting the left ventricle
What will iron deficiency impact?
Iron is a cofactor in many rxns (aconitase isomerization of citrate to isocitrate) and is incorporated in the Hb in RBC and heme proteins in ETC
