Exam 4 - Integrated Metabolism (STUDY SLIDES) Flashcards
Each organ has unique metabolic needs/functions which must maintain a constant supply of energy and preserving some for future needs.
Noted
Body uses __ and ___ to differentially control biochemical pathways within various organs in response to supply and demand.
nervous system and hormones
Main hormones include ___, ___, ___, ____, and growth hormone (in children).
insulin, glucagon, catecholamines, glucocorticoids
3 major tissues for metabolism include:
liver, adipose & skeletal muscle
The liver actively provides the ___ your body needs.
quick fuel (glucose)
Adipose tissue provides
long-term energy storage.
Skeletal muscle and the rest of your body constantly demand this energy. Brain consumes approximately ___ of glucose/day; 20% of the average diet.
90 g
The supply and demand of energy must be continuously provided via dietary intake or breakdown of stores to balance with the energy requirements of respiration, transport, motility, and synthesis of cells and tissues.
Average adult uses approximately (# of kCal/kg) of energy to insure proper health and to maintain proper weight.
24 kcal/kg
Several key biomolecules link the biochemical pathways for carbohydrates, lipids, and amino acids/proteins and the pathways they funnel into are tightly regulated and tissue specific.
What three are mentioned?
glucose-6-phosphate (G6-P), pyruvate, and acetyl coenzyme A or acetyl-CoA
They link the anabolic and catabolic pathways of carbohydrate metabolism to maintain a constant supply of energy to maintain homeostasis under constantly changing conditions.
Metabolic regulation at G6-P is critical, especially in the liver.
After ingestion of carbs, glucose taken up by liver is converted to G6-P by ___ using 1 ATP molecule, trapping glucose within hepatocytes
glucokinase
G6-P is metabolized in one of three pathways: _____ for energy storage, ____ for ATP production, or the pentose phosphate pathway for _____.
glycogenesis
glycolysis
NADPH and/or ribose’s production.
Pathway depends upon activation of ___ and ___ (enzymes?), substrate availability (G6-P, ATP, and NADP+) & allosteric effectors (ATP, AMP, fructose 2,6-bisphosphate [F2,6BP], hydrogen ions [H+], and [citrate]).
glycogen synthase and phosphofructokinase-1
What substrates are involved in the regulation of the G6P pathway?
G6-P, ATP, and NADP+
What allosteric inhibitors are involved in the G6P pathway?
ATP, AMP, fructose 2,6-bisphosphate [F2,6BP], hydrogen ions [H+], and [citrate]
The key enzymes in glycogenesis and glycolysis are predominantly regulated by (1) ___ and (2) ____ (phosphorylation); whereas the allosteric effectors fine-tune these pathways
hormone-stimulated
covalent modification
Regarding glycolysis and glycogeneiss, covalent modification is more or less synonymous with?
phosphorylation
Pentose phosphate pathway is primarily regulated by the availability of?
G6-P and NADP+
In the well-fed state, increased ATP and citrate, inhibit ____, the committing step of glycolysis (slowing the production of fructose 1,6-bisphosphate), leading to increased G6P
phosphofructokinase-1
stimulates glycogen synthase, leading to the formation of glycogen?
increased G6P
Increased G6P indirectly inhibits _____ thereby inhibiting glycogenolysis (glycogen degradation).
glycogen phosphorylase
Slide 15 for diagram on Glycolysis..
WHat are the key regulatory steps (enzymes)?
Hexokinase/glucokinase
Phosphofructo-kinase
Pyruvate kinase
With increase NADP+ and decreased NADPH, G6-P can be shuttled into the _____ to generate NADPH (reductive energy) used to synthesize a variety of biomolecules such as, fatty acids, cholesterol, nucleotides and other cofactors as needed.
pentose phosphate pathway
What are some biomolecules produced from pentose phosphate pathway?
fatty acids, cholesterol, nucleotides
and other cofactors as needed
With decreased NADP+ and increased NADPH, the pentose pathway (will/will not) operate regardless of the concentration of G6-P.
will not
Don’t confuse Fructose-2,6-Bisphosphate with?
Not the same as fructose-1,6-bisphosphate which represents the committing step to glycolysis
accelerates the synthesis of F-2,6-BP and inhibits its hydrolysis?
Fructose 6-phosphate
Fructose 6-phosphate is catalyzed to F-2,6-BP by?
phosphofructokinase-2
Abundance of fructose-6-phosphate leads to a higher concentration of F-2,6-BP, which in turn stimulates?
phosphofructokinase-1
This is called feed forward stimulation.
Eating breakfast stimulates _____/inhibits glycogen break-down in preparation for the next period of fasting
glycogen synthesis
↑ glucose stimulates beta cells in pancreas to release insulin, increasing absorption of glucose from blood, which dephosphorylates ____ (glycogenesis) and phosphorylates ____ (no glycogenolysis).
glycogen synthase
glycogen phosphorylase
slide 18
What hormone levels lead to ↑ glycogen synthase activity and ↓ glycogen phosphorylase activity?
↑ insulin, ↓ glucagon
After glycogen is replaced, then lipids will be synthesized using excess
carbohydrates.
If cholesterol biosynthesis is active, ____ from fatty acid metabolism can be synthesized into cholesterol.
excess acetyl-CoA
Once lipid biosynthesis commences, utilization of NADPH increases the NADP+/NADPH ratio favoring use of
pentose phosphate pathway.
Glycolysis is also stimulated by increase ___ which activates phosphofructokinase-2.
↑ [F2,6BP]
↓ blood glucose stimulates pancreas to release glucagon, which acts on ___ and stimulates cAMP.
liver G-protein
The cAMP (from the liver G-protein) phosphorylates _____ (no glycogen synthesis) and dephosphorylates glycogen phosphorylase (glycogenolysis)
glycogen synthase
2nd major branch point in metabolism is at ?
pyruvate
Pyruvate can be converted into lactate, ___, oxaloacetate, and/or acetyl-CoA, depending on energy needs.
alanine
What four chemicals can pyruvate be converted to, depending on energy needs?
Lactate
Alanine
Oxaloacetate
Acetyl-CoA
Pyruvate can undergo oxidative decarboxylation to enter __ and ultimately generate ATP when energy levels are low.
CAC
In liver, ___ and ___ can funnel into CAC or gluconeogenesis via pyruvate
Alanine & lactate
During starvation, ____can produce up to 160 g of glucose in a day (half from AA); half of the glucogenic glucose will be used by the brain.
gluconeogenesis
Of the 160 g of glucose maximally produced from gluconeogenesis, how much is from amino acids?
Half
As blood glucose levels stabilize and gluconeogenesis is not required, ____ can re-enter the glycolytic pathway at phosphoenolpyruvate or go back into mitochondria as malate, to enter the Citric Acid Cycle (CAC).
cytosolic oxaloacetate
↓energy inhibits pyruvate dehydrogenase kinase (PDK) (keeping ____ active) meaning that pyruvate is oxidatively decarboxylated to acetyl-CoA.
pyruvate dehydrogenase
If ↑energy, then ↑ [NADH] and [acetyl-CoA] activate ___ (turning off pyruvate dehydrogenase and CAC).
PDK (pyruvate dehydrogenase kinase)
___ and ___ stimulate pyruvate carboxylase, the first step of gluconeogenesis as alternative pathway.
↑ [ATP]
↑ [acetyl-CoA]
If ↓ O2 and anaerobic respiration becomes important, pyruvate can be converted to lactate by lactate dehydrogenase with oxidation of ONE ___ to ___, the latter being essential for sustaining glycolysis.
NADH
NAD+
Recall glycolysis: glucose gives 2 pyruvate + 2 ATP + 2 NADH + 2 H2O + 2 H+
In ___ conditions, ATP is derived solely from glycolysis.
anaerobic
↑ [NADH] stimulates ____ under anaerobic conditions.
lactate dehydrogenase
Also known as the Lactic Acid Cycle.
Cori Cycle
In the liver, ___ can be converted back to glucose for energy production via the Cori cycle.
lactate
When ↑ [lactate] get too high, inhibition blocks further conversion of pyruvate to ___
lactate
___ create the sensation of “burning” in muscles, which serves as a signal to the body to limit further use of these muscles.
↑ [lactate]
In muscle, pyruvate can convert toalanine via
alanine transaminase
Alanine cycle (analogous to Cori cycle) converts alanine back to pyruvate and glucose (gluconeogenesis) ____
in the liver.
Anaerobic conditions in muscle produce ___ or lactate.
alanine
Alanine produces ___ and is converted back to pyruvate in the process but the lactate pathway does not produce ___ when converted back to pyruvate.
urea
Alanine conserves ___ from glycolysis for electron transport if enough NAD+ is around.
NADH
3rd primary branch point of metabolic control
Acetyl-CoA
Coordinates carbohydrate, ketone, and fat/lipid pathways.
Acetyl-CoA
Acetyl-CoA required for production of
acetylcholine.
Acetyl-CoA can be oxidized via ___ to generate energy.
citric acid cycle (CAC)
When ↑ energy (High NADH/NAD+ ratio), NADH inhibits the citric acid cycle (CAC) via ____ & ____
isocitrate dehydrogenase
α-ketoglutarate dehydrogenase
When ↑ energy (High NADH/NAD+ ratio), Accumulation of ____ causes increase in succinyl-CoA that slows down the citric acid cycle (CAC).
FADH2
In fed state, excess acetyl-CoA can make cholesterol and/or FAs/TGs.
Where?
Liver
In the liver, during starvation, FA oxidation supplies energy for?
gluconeogenesis
In the liver, excess acetyl-CoA can be used for the synthesis of
ketone bodies.
amongst many other products in including FAs/TAGS/etc.
Ketone bodies cannot be used by the ___ and are exported and used as an alternate fuel for the brain, heart, and muscles.
liver
During fasting/starvation, brain reliant on ____ for up to 70% of energy requirements (especially prolonged starvation).
ketone bodies
In the Fed State, ↑ _____
condenses w/ acetyl-CoA producing citrate (first product of CAC)
and ↑ citrate is transported to cytoplasm for ____ (ATP-citrate lyase).
oxaloacetate
FA synthesis
In the Fed State, ↑ citrate activates acetyl-CoA carboxylase (promotes FA synthesis) and inhibits _____ (blocking glycolysis).
___ that backs up from blocked glycolysis can be used to make glycogen or sent through PPP to make NADPH for FA synthesis.
phosphofructokinase-1
G6-P
In the starvation state,
↑ acetyl-CoA from oxidation of FAs stimulates pyruvate carboxylase to promote ____
gluconeogenesis
↓citrate and intermediates of CAC and ↓ ATP/NADH/FADH2 promote active CAC and ____
oxidative phosphorylation.
CAC intermediates can also be used for the production of ___
AAs.
↓citrate/↑ palmitoyl-CoA (from lipolysis) prevent FA synthesis resulting in ↓ malonyl-CoA which favors formation of palmitoyl carnitine by carnitine palmitoyltransferase 1 (CPT1) and transport across mitochondrial membrane for ____
β-oxidation
Hormones involved in the Control of Metabolism?
Insulin
Glucagon
Catecholamines (norepinephrine & epinephrine)
Glucocorticoids
Anabolic hormone of the well-fed state?
insulin
Stimulates storage of excess nutrients (glycogen and triglycerides).
insulin
___ is composed of a leader sequence, A and B insulin chains, and C peptide.
Preproinsulin
slide 33
Removal of leader sequence produces ____.
proinsulin
Cleavage of ____ from proinsulin leads to active insulin.
C-peptide
___ present in equal concentrations as insulin making it a marker of insulin production.
C-peptide
Insulin release is stimulated by ↑ glucose and potentiated by ___
amino acids, stimulating protein synthesis
Insulin has 3 main targets?
liver, adipose tissue, & striated muscle.
In the liver, insulin stimulates?
↑ glycogenesis, FA synthesis, glycolysis, and PPP
In adipose tissue, insulin stimulates?
↑ glucose & FA uptake; triglyceride synthesis.
In skeletal muscles, insulin stimulates?
↑ glucose uptake, glycogenesis, protein synthesis.
Insulin does NOT influence glucose absorption in the β-cells of the pancreas, RBCs, intestinal mucosa, central nervous system (brain), or ?
nephrons of the kidney.
Insulin release from pancreatic β-cells is result of
↑ blood [glucose].
Glucose enters the ___ via the glucose transporter 2 (GLUT2) (passive transport); GLUT2 has a weak affinity for glucose ∴ favors glucose uptake only after meal when ↑ blood [glucose], rather than in fasting.
(insulin release)
β-cells
Following glucose oxidation, ↑ [ATP] stimulates ___ and depolarizes the cell membrane.
(insulin release)
K+ channels
____ opens voltage-gated Ca2+ channels and IP3, a second messenger, stimulate Ca2+ release from ER.
(insulin release)
Depolarization
____ triggers release of insulin.
↑ intercellular Ca2+
Insulin increases what 6 pathways in adipose tissue?
Glucose uptake (GLUT4)
Glycolysis (PFK1 to pyruvate)
Pentose pathway (G6P dehydrogenase to NADPH, ribose)
Pyruvate oxidation (pyruvate dehydrogenase to Acetyl-CoA)
Triglyceride lipolysis (lipoprotein lipase to absorb blood lipids)
Fatty acid/triglyceride synthesis (acetyl-CoA carboxylase to fatty acids)
Insulin downregulates what in the adipose tissue?
Lipolysis (hormone-sensitive lipase)
___ transport of glucose into cells is the rate-limiting step of glucose metabolism and is 10–20x increased in the plasma membranes of adipose and skeletal muscle cells in response to insulin.
GLUT4
Insulin upregulates what 4 pathways in the SKELETAL muscles?
Glucose uptake (GLUT4)
Glycolysis (PFK1 to F2,6BP)
Glycogen synthesis (glycogen synthase to store glycogen)
Protein synthesis (translation)
In the skeletal muscles, insulin downregulates?
Glycogenolysis (glycogen phosphorylase to stop glycogenolysis)
Hormone of fasting produced by pancreatic α-cells.
Glucagon
signals via G-protein coupled receptors and cyclic AMP.
Glucagon
Glucagon acts mainly on liver stimulating?
glycogenolysis, gluconeogenesis, and FA oxidation (but also effects lipolysis).
Leads to 2-3x ↑ in glucagon stimulate liver production of glucose from glycogen.
Hypoglycemia (↓ blood glucose)
↑ blood glucose, glucagon is reduced to __ of its normal level.
half
Glucagon also stimulates the release of ___ allowing insulin-sensitive cells to take up the released glucose.
insulin
The delicate balance of glucagon and insulin levels is how the body maintains ___ homeostasis under varying conditions.
glucose
Glucagon upregulates what pathways in the liver?
Gluconeogenesis
Glycogenolysis
Fatty acid oxidation
Glucagon downregulates what pathways in the liver?
Glycolysis
Glycogen synthesis
Fatty acid synthesis
Catecholamine hormones can provide almost immediate (within seconds) regulation of metabolism. E.g.?
norepinephrine and epinephrine
Stimulate glycogenolysis and glycolysis for the production of ATP in the muscle.
Catecholamines (norepinephrine and epinephrine)
Inhibit glycolysis in the liver and stimulate glycogenolysis to provide glucose for the blood.
Catecholamines (norepinephrine and epinephrine)
Synaptically released catecholamines have emerged as the main physiological pathway for the activation of ___ under conditions of fasting (a condition of chronic stress).
lipolysis
a substance (e.g., norepinephrine or acetylcholine) that transmits nerve impulses across a synapse (from one neuron to another or from a nerve to an innervated tissue).
Neurotransmitter
Organic compound (e.g., steroid or peptide) that is produced in one part of the body and travels to another part to exert its action usually through the blood
Hormone
Biochemicals, such as ___, can act as either a neurotransmitter or as a hormone depending on its specific utilization by the body.
catecholamines
Effects of epinephrine on metabolism… slide 44 for in depth chart
Check it
a chronic stress hormone that regulates metabolism.
Cortisol
Stimulates corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH).
Cortisol
Time frame of hours to days.
Cortisol has similar influence on metabolism as epinephrine but functions via activation of __ and ___ of genes rather than modulation of enzyme activity (slower timeline of response).
transcription and translation
Stimulates enzymes involved in gluconeogenesis in the liver, and in the breakdown of muscle protein leading to restored blood glucose.
cortisol
Increase in blood glucose is at the expense of muscle and bone and ultimately impairs immunological function.
DM is due to the imbalance in ___ metabolism and its effects on other metabolic pathways.
carbohydrate
no insulin made (patients usually skinny)
DM Type 1
insulin made but tissues resistant (patients usually overweight)
DM Type 2
Both lack signaling effect of insulin in the presence of glucagon.
DM Type 1
DM Type 2
Autoimmune destruction of β-cells leads to loss of insulin production.
Although the liver can make glucose, glycogen synthesis is impeded.
Type 1 Diabetes Mellitus
W/o insulin, gluconeogenesis is unrestrained, elevating blood glucose.
Type 1 Diabetes Mellitus
Muscle and fat cells cannot take up available blood glucose via GLUT4 (no insulin) and body cannot clear elevated blood glucose.
Type 1 Diabetes Mellitus
In Type 1 DM, ___ are starved for glucose even when present at very high levels in the blood.
Peripheral tissues (muscle and fat)
W/o insulin, glucagon secretion is uncoupled from blood glucose levels.
Type 1 Diabetes Mellitus
In Type 1 Diabetes Mellitus, Unopposed glucagon inhibits glycogen synthesis and stimulates ?
gluconeogenesis, glycogenolysis, and lipolysis.
↑ lipolysis leads to elevation of free fatty acids in the blood partly taken up by liver for lipoproteins leading to ↑ VLDL & LDL.
Type 1 Diabetes Mellitus
↑ lipolysis means ↑ ketone bodies leading ketoacidosis.
Type 1 Diabetes Mellitus
Only treatment is insulin injections.
Even with optimal control, damaging effects of elevated glucose and lipids eventually lead to medical complications.
Type 1 Diabetes Mellitus
Insulin produced, but target tissues resistant to its effects.
Type 2 Diabetes Mellitus
Body acts as if there is a relative deficiency of insulin, even when present at high levels.
Type 2 Diabetes Mellitus
As in type 1, ___ is unrestrained, and muscle/fat cells do not take up glucose via GLUT4.
gluconeogenesis
↑ blood glucose but liver still can make glycogen, and lipolysis is kept in check because insulin still present.
Type 2 Diabetes Mellitus
Fructose-2,6-bisphosphate:
Activates?
Inhibits?
activates glycolysis,
inhibits gluconeogenesis.
Glycolysis:
3 key regulating enzymes?
hexokinase, phosphofructokinase, pyruvate kinase
Gluconeogenesis:
3 key regulating enzymes?
fructose-1,6-BP,
PEP carboxykinase,
pyruvate carboxylase.
