Ch. 9: Carbohydrate Metabolism I: Glycolysis, Glycogen, Gluconeogenesis, and The Pentose Phosphate Pathway Flashcards
what is glucose entry into most cells driven by and independent of?
driven by concentration
independent of sodium
value: normal glucose concentration in peripheral blood
5.6 mM
normal range: 4-6 mM
names + what are the most significant and why: 4 glucose transporters
GLUT 1 through GLUT 4
GLUT 2 and GLUT 4 are the most significant because they are located only in specific cells and are highly regulated
defn: GLUT 2
a low-affinity transporter in hepatocytes and pancreatic cells
function process (2): GLUT 2
- after a meal, blood traveling through the hepatic portal vein from the intestine is rich in glucose
- GLUT 2 captures the excess glucose primarily for storage
what happens when the glucose concentration drops below the Km for the GLUT 2?
much of the remainder bypasses the liver and enters the peripheral circulation
what is the Km of GLUT 2 and what impact does this have?
Km: quite high (~15 mM)
the liver will pick up glucose in proportion to its concentration in the blood
aka: the liver will pick up excess glucose and store it preferentially after a meal, when blood glucose levels are high
what 2 items serve as the glucose sensor for insulin release in the Beta-islet cells of the pancreas?
- GLUT 2
- glycolytic enzyme glucokinase
location + func + process: GLUT 4
location: in adipose tissue and muscle
func: responds to the glucose concentration in peripheral blood
process: the rate of glucose transport in these adipose and muscle is increased by insulin, which stimulates the movement of additional GLUT 4 transporters to the membrane by a mechanism involving exocytosis
what is the Km of GLUT 4 and what is the impact of this?
close to normal glucose levels in blood (~5 mM)
this means that the transporter is saturated when blood glucose levels are just a bit h igher then normal
what occurs with GLUT 4 when a person has high blood sugar concentrations?
the GLUT4s will still permit only a constant rate of glucose influx because they will be saturated
how can cells with GLUT 4 transporters increase their glucose intake?
by increasing the number of GLUT 4 transporters on their surface
diagram: insulin regulation of glucose transport in muscle and adipose cells
what is diabetes mellitus caused by?
a disruption of the insulin/GLUT 4 mechanism
what is the difference between type 1 diabetes and type 2 diabetes?
TYPE 1: insulin is absent and cannot stimulate the insulin receptor
TYPE 2: the receptor becomes insensitive to insulin and fails to bring GLUT 4 transporters to the cell surface
what is true in both type 1 and type 2 diabetes?
blood glucose increases leading to immediate symptoms and long-term symptoms
what are 3 immediate symptoms of diabetes? what are 4 long-term symptoms of diabetes?
IMMEDIATE:
1. increase urination
2. increased thirst
3. ketoacidosis
LONG-TERM:
1. blindness
2. heart attacks
3. strokes
4. nerve damage
how does transport respond to insulin and how does transport occur without insulin? (2)
- basal levels of transport occur in all cells independently of insulin
- the transport rate increases in adipose tissue and muscle when insulin levels rise
what is the relationship with muscle and adipose tissue to glucose?
MUSCLE: stores excess glucose as glycogen
ADIPOSE TISSUE: requires glucose to form dihydroxyacetone phosphate (DHAP), which is converted to glycerol phosphate to store incoming fatty acids as triacylglycerols
can all cells carry out glycolysis?
yes
why is glycolysis the only energy-yielding pathway available in red blood cells?
red blood cells lack mitochondria, which are required for the citric acid cycle, electron transport chain, oxidative phosphorylation, and fatty acid metabolism (beta-oxidation)
what is the 1 major monosaccharide that enters the glycolysis pathway? what other 2 feed into it?
MAJOR: glucose
FEEDERS: 1. galactose 2. fructose
what diseases are caused by the complete absence of any enzyme in glycolysis?
none! glycolysis is necessary in every cell of the body
being unable to carry out glycolysis is incompatible with life
there are a few PARTIAL enzyme defects, but even these are rare
defn: glycolysis
a cytoplasmic pathway that converts GLUCOSE into TWO PYRUVATE molecules, releasing a modest amount of energy captured in 2 substrate-level phosphorylations and one oxidation reaction
how is the process of glycolysis affected if a cell has mitochondria and oxygen?
if either mitochondria or oxygen is lacking?
cell has both: the energy carriers produced in glycolysis (NADH) can feed into the aerobic respiration pathway to generate energy for the cell
if either lacking: glycolysis may occur anaerobically, although some available energy is lost
in what body part might mitochondria be lacking for glycolysis? what about oxygen?
mitochondria: erythrocytes
oxygen: exercising skeletal muscle
in what circumstance does glycolysis serve as an intermediate for another pathway?
in the liver, glycolysis is part of the process by which excess glucose is converted to fatty acids for storage
diagram: glycolysis
what are the 5 main enzymes of glycolysis that the MCAT focuses on?
- hexokinase (glucokinase in liver)
- phosphofrutokinases
- glyceraldehyde-3-phosphate dehydrogenase
- 3-phosphoglycerate kinase
- pyruvate kinase
what are the first steps of glucose metabolism in any cell? (2)
- transport across the membrane and 2. phosphorylation by kinase enzymes inside the cell to prevent glucose form leaving via the transporter
how does glucose enter the cell and what happens to glucose?
enters the cell: by facilitated diffusion or active transporter
either way: kinases convert glucose to glucose-6-phosphate
what is the result of the fact that GLUT transporters are specific for glucose, and not phosphorylated glucose?
the glucose gets “trapped” inside the cell and cannot leak out
location + compound that affects it: hexokinase vs. glucokinase
HEXO = 1. widely distributed in tissues
2. inhibited by its product, glucose-6-phopshate
GLUCO = 1. found only in liver cells and pancreatic beta=islet cells
2. induced by insulin in the liver
table: hexokinase vs. glucokinase + what else do these coincide with
coincide with the differences between the glucose transporters in these tissues
of all the enzymes the MCAT is going to test you on, the rate-limiting enzymes for each process are at the top. what are these for
- glycolysis
- fermentation
- glycogenesis
- glycogenolysis
- gluconeogenesis
- pentose phosphate pathway
- glycolysis = phosphofructokinase-1
- fermentation: lactate dehydrogenase
- glycogenesis: glycogen synthase
- glycogenolysis: glycogen phosphorylase
- gluconeogenesis: fructose-1,6-bisphosphate
- pentose phosphate pathway: glucose-6-phosphate dehydrogenase
defn + func: phosphofructokinase-1 (PFK-1)
defn: the rate-limiting enzyme and main control point in glycolysis
func: fructose 6-phosphate is phosphorylated to fructose 1,6-bisphosphate using ATP
what inhibits and activates PFK-1 and why does this make sense?
inhibited by: ATP and citrate
activated by: AmP
makes sense because the cell should turn off glycolysis when it has sufficient energy (high ATP) and turn on glycolysis when it needs energy (high AMP)
citrate is an intermediate of the citric acid cycle so high levels of citrate also imply that the cell is making enough energy
what stimulates and inhibits PFK-1 in hepatocytes and how (summary)?
stimulates: insulin
inhibits: glucagon
by an indirect mechanism involving PFK-2 and fructose 2,6-bisphosphate
what is the indirect mechanism by which PFK-1 is stimulated (2) and inhibited (1) in hepatocytes?
stimulates:
1. insulin activates PFK2, which converts a tiny amount of fructose 6-phosphate to fructose 2,6-bisphosphate (F2,6-BP)
- F2,6-BP activates PFK-1
inhibits:
1. glucagon inhibits PFK-2, lowering F2,6-BP and thus inhibiting PFK-1
where is PFK-2 mostly found?
in the liver
what does PFK-2 allow for by activating PFK-1?
allows these cells to override the inhibition caused by ATP so that glycolysis can continue even when the cell is energetically satisfied
thus, the metabolites of glycolysis can be fed into the production of glycogen, fatty acids, and other storage molecules rather than just being burned to produce ATP
func + impact: glyceraldehyde-3-phosphate dehydrogenase
func: catalyzes an oxidation and addition of inorganic phosphate (Pi) to its substrate, glyceraldehyde 3-phosphate
impact: results in the production of a high-energy intermediate 1,3-biphosphoglycerate and the reduction of NAD+ to NADH
what can happen to the NADH produced from the function of glyceraldehyde-3-phosphate dehydrogenase IF glycolysis is aerobic?
it can be oxidized by the mitochondrial ETC, providing energy for ATP synthesis by oxidative phosphorylation
func: 3-phosphoglycerate kinase
transfers the high-energy phosphate from 1,3-bisphosphoglycerate to ADP, forming ATP and 3-phosphoglycerate
defn + ex: substrate-level phosphorylation
a reaction in which ADP is directly phosphorylated to ATP using a high-energy intermediate
ex: the reaction that 3-phosphoglycerate kinases catalyzes
what are the differences between substrate-level phosphorylations and oxidative phosphorylation? (2)
substrate-levels are
- not dependent on oxygen
- are the only means of ATP generation in an anaerobic tissue
func: pyruvate kinase
catalyzes a substrate-level phosphorylation of ADP using the high-energy substrate phosphoenolpyruvate (PEP)
what activates pyruvate kinase?
what type of activation is this?
fructose 1,6-bisphosphate from the PFK-1 reaction
type: feed-forward activation
defn + ex: feed-forward actiation
the product of an earlier reaction of glycolysis (fructose 1,6-bisphosphate) stimulates, or prepares, a later reaction in glycolysis (by activating pyruvate kinase)
what occurs in the absence of oxygen?
fermentation
defn + func: lactate dehydrogenase
defn: the key fermentation enzyme in mammalian cells
func: 1. oxidizes NADH to NAD+, replenishing the oxidized coenzyme for glyceraldehyde 3-phosphate dehydrogenase
2. reduces pyruvate to lactate
when would glycolysis stop without mitochondria and oxygen?
what prevents this?
when all the available NAD+ had been reduced to NADH
prevented by lactate dehydrogenase reducing pyruvate to lactate and oxidizing NADH to NAD+
why is there no net loss of C in the process performed by lactate dehydrogenase?
pyruvate and lactate are both 3-C molecules
when is lactate production low and high?
LOW: in aerobic tissues, lactate does not normally form in significant amounts
HIGH: when oxygenation is poor (exercise, heart attack, stroke), most cellular ATP is generated by anaerobic glycolysis and lactate production increases
defn: fermentation in yeast cells
the conversion of pyruvate (3 C’s) to ethanol (2 C’s) and carbon dioxide (1 C)
diff + similarity: mammalian and yeast fermentation
diff: end products
similarity: result (replenishing NAD+)
what does it mean that glycolysis serves as a crossroads for a number of metabolic processes?
the intermediates of glycolysis are often used to link different pathways during catabolism and anabolism
what 3 intermediates of glycolysis are important?
- dihydroxyacetone phosphate (DHAP)
- 1,3-bisphosphoglycerate (1,3-BPG)
- phosphoenolpyruvate (PEP)
func + where does it come from + what can it turn into: dihydroxyacetone phosphate (DHAP)
func: used in hepatic and adipose tissue for triaclyglycerol synthesis
formed from: fructose 1,6-bisphosphate
can be isomerized to glycerol 3-phosphate, which can then be converted to glycerol, which is the backbone of triacylglycerols
char + func: 1,3-bisphosphoglycerate (1,3-BPG) and phosphoenolpyruvate (PEP)
high-energy intermediates
func: used to generate ATP by substrate-level phosphorylation (the only ATP gained in anaerobic respiration)
mnemonic: irreversible steps of glycolysis
How Glycolysis Pushes Forward the Process: Kinases
Hexokinase
Glucokinase
PFk-1
Pyruvate Kinase
how is ATP produced in erythrocytes and how much ATP is yielded?
anaerobic glycolysis is the only pathway for ATP production, yielding a net 2 ATP per glucose
func + loc: biphosphoglycerate mutase
loc: red blood cells
produces 2,3-bisphosphoglycerate (2,3-BPG) from 1,3-BPG in glycolysis by moving the phosphate from the 1-position to the 2-position
defn: mutases
enzymes that move a functional group from one place in a molecule to another
func in red blood cells: 2,3-BPG
binds allosterically to the beta-chains of hemoglobin A (HbA) and decreases its affinity for oxygen
what impact does 2,3-BPG have on the oxygen dissociation curve for HbA? + diagram
rightward shift: sufficient to allow unloading of oxygen in tissues, but still allows 100% saturation in the lungs
far shift: abnormal increase in erythrocyte 2,3-BPG. such a far shift that HbA is not fully saturated in the lungs
what 6 things does adaptation to high altitudes (low pO2) involve?
- increased respiration
- increased oxygen affinity for hemoglobin (initial)
- increase glycolysis rate
- increase 2,3-BPG in RBC (over 12-24 hrs)
- normalized oxygen affinity for hemoglobin restored by the increased 2,3-BPG
- increased hemoglobin (over days to weeks)
what 4 physiological changes promote a right shift of the oxygen dissociation curve? when do these occur? + mnemonic
- high 2,3-BPG
- low pH
- high [H+]
- High pCO2
during exercise
mnemonic: Exercise is the RIGHT thing to do
what is the impact of the fact that 2,3 BPG binds to HbA, but does not bind well to fetal hemoglobin (HbF)? (2)
HbF has a higher affinity for oxygen than maternal HbA
and allows for transplacental passage of oxygen from mother to fetus
diagram: galactose metabolism
diagram: fructose metabolism
what is an important source of galactose in the diet?
lactose: the disaccharide present in milk
what does lactase do to lactose?
lactase hydrolyzes lactose to galactose and glucose
defn: lactase
a brush-border enzyme of the duodenum
how do galactose and other monosaccharides reach the liver?
through the hepatic portal vein
process (2): galactose metabolism
- once transported into tissues, galactose is phosphorylated by galactokinase, trapping it in the cell
- the resulting galactose 1-phosphate is converted to glucose 1-phosphate by galactose-1-phosphate uridyltransferase and an epimerase
defn: epimerases
enzymes that catalyze the conversion of one sugar epimer to another
what is fructose found in?
honey, fruit, and as part of the disaccharide sucrose (common table sugar)
process (4): fructose metabolism
- sucrose is hydrolyzed by the duodenal brush-border enzyme sucrase
- the resulting monosaccharides, glucose and fructose, are absorbed into the hepatic portal vein
- the liver phosphorylates fructose using fructokinase to trap it in the cell
- the resulting fructose 1-phosphate is then cleaved into glyceraldehyde and DHAP by aldolase B (smaller amounts are metabolized in renal proximal tubules)
Why does a high-fructose drink supply a quick source of energy in both aerobic and anaerobic cells?
because DHAP and glyceraldehyde, the products of fructose metabolism, are downstream from the key regulatory and rate-limiting enzyme of glycolysis (PFK-1)
func + char + what CAN’T it do + diagram: pyruvate dehydrogenase complex (PDH) reaction
func: when pyruvate from aerobic glycolysis enters mitochondria, it may be converted to acetyl-CoA
- for entry into the citric acid cycle if ATP is needed OR
- for fatty acid synthesis if sufficient ATP is present
char: irreversible
CANNOT: be used to convert acetyl-CoA to pyruvate or to glucose
what is pyruvate dehydrogenase activated by in the liver? in the nervous system?
LIVER: activated by insulin
NERVOUS SYSTEM: not responsive to hormones
what do high insulin levels signal to the liver and what is the livers response (2)?
high insulin levels signal to the liver: that the individual is in a well-fed state
thus
- the liver should not only burn glucose for energy, but also
- shift the fatty acid equilibrium toward production and energy, rather than oxidation
what medical conditions things can a deficiency in thiamine (vitamin B1) result in and what are these 2 conditions characterized by?
- BERIBERI = congestive heart failure or nerve damage
- WERNICKE-KORSAKOFF SYNDROME = difficulty walking, uncoordinated eye movements, confusion, and memory disturbances
what can occur when you give glucose to someone with thiamine deficiency? why?
how do you prevent this?
can lead to severe lactic acidosis and other metabolic derangements
because pyruvate cannot be converted into acetyl-CoA without the vitamin
fix: thiamine must be given before an infusion of glucose in those with thiamine deficiency (like alcoholics)
what are the 3 possible fates of pyruvate and how does it arrive at these fates?
conversion to:
- acetyl-CoA by PDH
- lactate by lactate dehydrogenase
- oxaloacetate by pyruvate carboxylase
pyruvate dehydrogenase is actually a complex of enzymes carrying out multiple reactions in succession, what 5 cofactors and coenzymes are required by this complex? what can insufficient amounts of any of these result in?
- thiamine pyrophosphate
- lipoic acid
- CoA
- FAD
- NAD+
insufficient amounts: can result in metabolic derangements
what is pyruvate dehydrogenase inhibited by?
its product, acetyl-CoA
the buildup of acetyl-CoA (happens during Beta-oxidation) causes a shift in metabolism. what effect does this have?
pyruvate is no longer converted into acetyl-CoA (to enter the TCA cycle), but rather into oxaloacetate (to enter gluconeogenesis)
defn + func: glycogen
defn: a branched polymer of glucose
func: a storage form of glucose
where do glycogen synthesis and degradation primarily occur?
in the liver and skeletal muscle
how is glycogen stored in the cytoplasm?
as granules
structure + diagram: glycogen granules
each has a central protein core with polyglucose chains radiating outward to form a sphere
how are the structures of glycogen granules affected by being composed of linear chains vs. branched chains?
LINEAR = highest density of glucose near the core
BRANCHED = glucose density is highest at the periphery of the granule, allowing more rapid release of glucose on demand
what is the difference between glycogen stored in the liver and glycogen stored in muscle?
LIVER: a source of glucose that is mobilized/broken down between meals to prevent low blood sugar/maintain a constant level of glucose in the blood
MUSCLE: stored as an energy reserve for muscle contraction (for during vigorous exercise)
how do plants store excess glucose?
in long alpha-linked chains of glucose called starch!
defn: glycogenesis
the synthesis of glycogen granules
process summary (5) + diagram: glycogenesis
- begins with a core protein called glycogenin
- glucose addition to a granule begins with glucose-6-phosphate, which is converted to glucose 1-phosphate
- this glucose 1-phosphate is then activated by coupling to a molecule of uridine diphosphate (UDP)
- this permits its integration into the glycogen chan by glycogen synthase
- this activation occurs when glucose 1-phosphate interacts with uridine triphosphate (UTP), forming UDP-glucose and a pyrophosphate (PPi)
defn + func: glycogen synthase
defn: the rate-limiting enzyme of glycogenesis
func: forms the alpha-1,4 glycosidic bond found in the linear glucose chains of the granule
what stimulates glycogen synthase? what inhibits it? (2 each)
STIMULATED BY: glucose 6-phosphate and insulin
INHIBITED BY: epinephrine and glucagon (through a protein kinase cascade that phosphorylates and activates the enzyme)
func: branching enzyme (glycosyl alpha-1,4:alpha-1,6 transferase)
responsible for introducing alpha-1,6-linked branches into the granule as it grows
diagram + steps (4): how the branch is introduced by branching enzymes
- glycogen synthase makes a linear alpha-1,4-linked polyglucose chain
- branching enzyme hydrolyzes an alpha-1,4 bond to release a block of oligoglucose
- branching enzyme transfers the oligoglucose unit and attaches it with an alpha-1,6 bond to create a branch
- glycogen synthase extends both branches
defn: oligoglucose
a few glucose molecules bonded together in a chain
mnemonic: alpha-1,4 vs. alpha-1,6
alpha-1,4: keeps the same branch moving “4ward”
alpha-1,6: puts a branch in the MIX
defn: glycogenolysis
the process of breaking down glycogen
what is the rate-limiting enzyme to glycogenolysis? what does this enzyme produce?
glycogen phosphorylase
this enzyme produces glucose 1-phosphate
func: phosphorylase
breaks bonds using an inorganic phosphate instead of water
what happens to the glucose 1-phosphate produced by glycogen phosphorylase in glycogenolysis?
it is converted to glucose 6-phosphate by the same mutase used in glycogen synthesis
func: glycogen phosphorylase
breaks alpha-1,4 glycosidic bonds, releasing glucose 1-phosphate from the periphery of the granule
why and where does glycogen phosphorylase stop?
stops when it nears the outermost branch points of the granule because it cannot break alpha-1,6 bonds
what is glycogen phosphorylase activated by in the liver? in skeletal muscle? why?
what is it inhibited by?
LIVER: by glucagon (so that glucose can be provided for the rest of the body)
SKELETAL MUSCLE: activated by AMP and epinephrine, which signal that the muscle is active and requires more glucose
INHIBITED BY: ATP
defn + func: debranching enzyme (glucosyl alpha-1,4:alpha-1,4 transferase and alpha-1,6 glucosidase)
defn: a two enzyme complex
func: deconstructs the branches in glycogen that have been exposed by glycogen phosphorylase
steps (4) + diagram: debranching enzyme function
- Glycogen phosphorylase releases glucose 1-P from the periphery of the granule until it encounters the first branch point
- debranching enzyme hydrolyzes the alpha-1,4 bond nearest the branch point
- debranching enzyme transfers the oligoglucose unit that is released to the exposed end of the other chain and forms a new alpha-1,4 bond
- Debranching enzyme hydrolyzes the alpha-1,6 bond, releasing the single residue at the branch point as free glucose
what is unique about the free glucose that is released when debranching enzyme hydrolyzes the alpha-1,6 bond?
it represents the only free glucose produced DIRECTLY in glycogenolysis
what 3 factors do the clinical features of a metabolic glycogen defect depend on?
- which enzyme is affected
- the degree to which that enzyme’s activity is decreased
- which isoform of the enzyme is affected
defn + ex: isoforms
slightly different versions of the same protein
ex: in terms of glycogen enzymes, there are often different isoforms of the enzymes in the liver and muscle
why are these deficiencies termed glycogen storage diseases?
they are all characterized by accumulation or lack of glycogen in one or more tissues
how does the liver maintain glucose levels in blood during fasting? (2)
- glycogenolysis
OR - gluconeogenesis
what other organ also performs gluconeogenesis, but to a smaller degree than the liver?
the kidney
what 2 things promote glycogenolysis and gluconeogenesis? why?
what one thing inhibts them? why?
PROMOTED BY: 1. glucagon 2. epinephrine –> act to raise blood sugar levels
INHIBITED BY: 1. insulin –> acts to lower blood sugar levels
what happens in the first 12 hours of fasting? what about by 24 hours?
12 hours: glycogen reserves drop dramatically and gluconeogenesis increases
24 hours: gluconeogenesis is the sole source of glucose
what are the 3 important substrates for gluconeogenesis and where do they come from?
- glycerol 3-phosphate (from stored fats, or triacylglycerols, in adipose tissue)
- lactate (from anaerobic glycolysis)
- glucogenic amino acids (from muscle proteins)
defn: glucogenic amino acids vs. ketogenic amino acids
GLUCOGENIC = all except leucine and lysine = can be converted into intermediates that feed into gluconeogenesis
KETOGENIC = can be converted into ketone bodies, which can be used as an alternative fuel, particularly during periods of prolonged starvation
true or false: amino acids can be both glucogenic and ketogenic
true
why are most fatty acids not a major source of glucose?
because most of them are metabolized solely to acetyl-CoA (which cannot be converted back to glucose)
what is one exception to the fact that most fatty acids are not a major source of glucose?
fatty acids with an odd number of carbon atoms, which yield a small amount of propionyl-CoA, which is glucogenic
what are the 3 important gluconeogenic intermediates and then enzymes that convert them into glycolytic intermediates (and what do they turn into)?
- lactate –> converted to pyruvate by lactate dehydrogenase
- alanine –> converted to pyruvate by alanine aminotransferase
- glycerol 3-phoshate –> converted to dihydroxyacetone phosphate (DHAP) by glycerol-3-phosphate dehydrogenase
diagram: gluconeogenesis
what are the 4 important enzymes from gluconeogenesis that are important to remember? (category + individuals)
category: those required to catalyze reactions that circumvent the irreversible steps of glycolysis in the liver (those catalyzed by glucokinase, PFK-1, and pyruvate kinase)
- pyruvate carboxylase
- phosphoenolpyruvate carboxykinase (PEPCK)
- fructose-1,6-bisphosphatase
- glucose-6-phosphatase
defn + what activates it + product: pyruvate carboxylase
a mitochondrial enzyme
activated by acetyl-CoA (from Beta-oxidation)
product: oxaloacetate (OAA)
char + what happens to (2): oxaloacetate
char: 1. citric acid cycle intermediate
2. cannot leave the mitochondrion
what happens to: 1. reduced to malate (which can leave the mitochondrion via the malate-aspartate shuttle)
2. once in the cytoplasm, malate is oxidized to OAA
why is it important that acetyl-CoA activates pyruvate carboxylase?
- acetyl-CoA INHIBITS pyruvate dehydrogenase because a high level of acetyl-CoA implies that the cell is energetically satisfied and need not run the citric acid cycle in the forward reaction (the cell should stop burning glucose)
- pyruvate will be shunted through pyruvate decarboxylase to help generate additional glucose through gluconeogenesis
- the source of acetyl-CoA here is not from glycolysis and pyruvate dehydrogenase, but from fatty acids
what must happen to produce glucose in the liver during gluconeogenesis and why?
fatty acids must be burned to provide energy, to stop the forward flow of the citric acid cycle, and produce massive amounts of OAA that can eventually lead to glucose production for the rest of the body
location + induced by? (2) + func: phosphoenolpyruvate carboxykinase (PEPCK)
in: the cytoplasm
induced by: glucagon and cortisol (which generally act to raise blood sugar levels)
func: converts OAA to phosphoenolpyruvate (PEP) in a reaction that requires GTP. PEP then continues in the pathway to fructose 1,6-bisphosphate
what is the combination of pyruvate carboxylase and PEPCK used for?
to circumvent the action of pyruvate kinase by converting pyruvate back into PEP
defn + loc + func: fructose-1,6-bisphosphatase
loc: cytoplasm
defn: a key control point of gluconeogenesis and represents the rate-limiting step of the process
func: reverses the action of PFK-1 (the rate-limiting step of glycolysis) by removing phosphate from fructose 1,6-bisphosphate t o produce fructose 6-phosphate
what do phosphatases commonly oppose?
kinases
what activates (1) and inhibits (2) fructose-1,6-bisphosphatase?
why does this make sense?
activated by: ATP
inhibited by: AMP and fructose 1,6-bisphosphate
high levels of ATP = the cell is energetically satisfied enough to produce glucose for the rest of the body, whereas high levels of AMP imply that a cell needs energy and cannot afford to produce energy for the rest of the body before satisfying its own requirements
what is fructose 2,6-bisphosphate (F2,6-BP) often though of as? why?
a marker for satisfactory energy levels in liver cells
it helps these cells override the inhibition of PFK-1 that occurs when high levels of acetyl-CoA are formed, signaling to the liver cell that it should shift its function from burning t storing fule
what produces F2,6-BP and what does F2,6-BP control (2)?
produced by: PFK-2
controls: gluconeogenesis and glycolysis (in the liver)
Recall: PFK-2 is activated by insulin and inhibited by glucagon. What affect does this have on F2,5-BP?
GLUCAGON = lowers F2,6-BP and stimulates gluconeogenesis
INSULIN = increases F2,6-BP and inhibits gluconeogenesis
location: glucose-6-phosphatase
found only in the lumen of the endoplasmic reticulum in liver cells
it is transported into the ER and free glucose is transported back into the cytoplasm, where it can diffuse out of the cell using GLUT transporters
what does the absence of glucose-6-phosphatase in skeletal muscle mean?
muscle glycogen cannot serve as a source of blood glucose and is for use only within the muscle
func: glucose-6-phosphatase
used to circumvent glucokinase and hexokinase which converts glucose to glucose 6-phosphate
what are most amino acids converted to?
- citric acid cycle intermediates
- then malate, following the same path from there to glucose
why is gluconeogenesis linked to fatty acid oxidation?
because gluconeogenesis requires acetyl-CoA to occur (to inhibit pyruvate dehydrogenase and stimulate pyruvate carboxylase) and requires expenditure of ATP provided by beta-oxidation
why does the source of acetyl-CoA have to be fatty acid oxidation and cannot be glycolysis?
If the source of acetyl-CoA was glycolysis, this would just burn the glucose that is being generated in gluconeogenesis
is glucose produced by hepatic gluconeogenesis an energy source for liver?
no
what do adipose tissues release during periods of low blood sugar and how?
adipose tissue releases these fatty acids by breaking down triacylglycerols to glycerol (which can also be converted to the gluconeogenic intermediate DHAP) and free fatty acids
the acetyl-CoA from fatty acids cannot be converted into glucose, what can it be converted into?
ketone bodies as an alternative fuel for cells, including the brain
what are extended periods of low blood sugar usually accompanied by in blood?
high levels of ketones in the blood
what can ketone bodies be thought of as?
a transportable form of acetyl-CoA that is primarily utilized in periods of extended starvation
why can’t red blood cells carry out aerobic metabolism?
what do they do instead?
because they lack mitochondria
instead: pyruvate is converted to lactic acid to regenerate NAD+
where does the lactate created by red blood cells go? what happens to it there? why does it have to be removed from the bloodstream?
it must be removed from the bloodstream to avoid acidifying the blood
so RBCs deliver the lactate to the liver, where it can be converted back into pyruvate and, through gluconeogenesis, become glucose for the red blood cells to use
defn: Cori cycle
glucose is converted to lactate in red blood cells and lactate is converted to glucose in liver cells
aka+ location + two main functions: pentose phosphate pathway (PPP)
aka: hexose monophosphate (HMP) shunt
loc: occurs in the cytoplasm of all cells
func: 1. production of NADP
2. serving as a source of ribose 5-phosphate for nucleotide synthesis
what does the first part of the PPP begin with?
end with?
reversible or irreversible?
produces?
what important enzyme is involved?
begins with: glucose 6-phosphte
ends with: ribulose 5-phopshate
irreversible
produces: NADPH
involves the rate-limiting enzyme: glucose-6-phosphate dehydrogenase (G6PD)
what induces G6PD and why?
insulin because the abundance of sugar entering the cell under insulin stimulation will be shunted into both fuel utilization pathways (glycolysis and aerobic respiration), as well as fuel storage pathways (fatty acid synthesis, glycogenesis, and the PPP)
what is the PPP inhibited by? what is it activated by?
inhibited by: its product, NADPH
activated by: one of its reactants NADP+
diagram: pentose phosphate pathway
what type of disorder is G6PD deficiency? what impact does this have?
an X-linked disorder + the most common inherited enzyme defect in the world
these people are susceptible to oxidative stress, especially in red blood cells
why are individuals with G6PD deficiency susceptible to oxidative stress?
the PPP is critically important in maintaining levels of glutathione, which helps break down peroxides
what impact does ingestion of certain oxidizing compounds (certain antibiotics or antimalarials) or infections have on G6PD deficient patients?
can lead to high concentrations of reactive oxygen species, causing red blood cell lysis
why is G6PD deficiency sometimes referred to as favism?
fava beans are a highly oxidizing food that will cause hemolysis in these individuals
what does the second part of the PPP begin with?
represent as a whole?
begins with: ribulose 5-phosphate
represents: a series of reversible reactions that produce an equilibrated pool of sugars for biosynthesis, including ribose 5-phosphate for nucleotide synthesis
why can intermediates from the second part of the PPP feed back into glycolysis?
because fructose 6-phosphate and glyceraldehyde 3-phosphate are among the sugars produced
true or false: pentoses can be made from glycolytic intermediates without going through the G6PD reaction
true!
what 2 enzymes accomplish most of the conversions of intermediates talked about above?
- transketolase
- transaldolase
func + char: NAD+
func: acts as a high-energy electron acceptor from a number of biochemical reactions
char: potent oxidizing agent because it helps another molecule be oxidized (and thus is reduced itself during the process)
what is produced from the reduction of NAD+? what happens to this product?
product: NADH
feeds into the ETC to indirectly produce ATP
func + char: NADPH
func: primarily acts as an electron donor in a number of biochemical reactions
char: a potent reducing agent because it helps other molecules be reduced (and thus is oxidized itself during the process)
what 3 functions do cells require NADPH for?
- biosynthesis (mainly of fatty acids and cholesterol)
- assisting in cellular bleach production in certain white blood cells, thereby contributing to bactericidal activity
- Maintenance of a supply of reduced glutathione to protect against reactive oxygen species (acting as the body’s natural antioxidant)
why is the function of NADPH “Maintenance of a supply of reduced glutathione to protect against reactive oxygen species (acting as the body’s natural antioxidant)” important?
Important in protecting cells from free radical oxidative damage caused by peroxides
name: H2O2
what is H2O2 produced from? what can it break apart into?
name: hydrogen peroxide
produced as: a byproduct in aerobic metabolism
can break apart to form: hydroxide radicals, OH*
func: free radicals
can attack lipids, including those in the phospholipids of the membrane
what happens to the lipids produced from free radicals when they are oxidized?
where is this especially true?
they lose their function and can weaken the membrane, causing cell lysis
especially true in red blood cells, which contain high levels of oxygen
what happens to the high levels of oxygen in red blood cells when they are oxidized? what oxidizes them?
oxidized by: other free radicals
becomes: superoxide radical O2
what happens if free radicals damage DNA?
potentially cancer
defn: glutathione
a reducing agent that can help reverse radical formation before damage is done to the cell
summary: NAD+ vs. NADPH
NAD+ = an energy carrier
NADPH = used in biosynthesis, the immune system, and to help prevent oxidative damage
