macronutrients exam 2

insulin summary

-released by pancreatic b cells

-fed state

-lower blood glucose

-insulin signals GLUT4 in skeletal muscle and adipose tissue

glucagon summary

-released by pancreatic alpha cells

-fasting state

-increases blood glucose

-binds to glucagon receptors (G-protein coupled)

epinephrine

-secreted from adrenal glands

-catecholamine

-released in "flight or fight" conditions

-released in response to vigorous exercise (considered a stress)

role in glucose metabolism

-stimulates breakdown of glycogen (liver and skeletal muscle)

-increases glycolysis (skeletal muscle)

-binds to adrenergic receptors- G protein coupled receptors

GLUT4 and exercise

contraction of muscle contraction acts as another trigger for GLUT4 to get to membrane

-why diabetes should exercise

-naturally "lowers" blood sugar

cortisol

-secreted from adrenal glands

-glucocorticoid (from cholesterol)

-stress hormone

role in glucose metabolism

-glycogen breakdown (liver and skeletal muscle)

-gluconeogenesis (liver)

-also stimulates protein breakdown in skeletal muscle

-secreted during prolonged fasting, vigorous exercise, illness, injury

-binds to intracellular receptors- need protein in blood to get into cell

G-protein reaction

cascade reaction used by glucagon and epinephrine

-hormone binds to G protein

-G protein binds to adenylyl cyclase (triggers conversion of ATP into cAMP)

-cAMP acts as a SECOND messenger and activates protein kinase A

-protein kinase A is directly involved in regulating enzymes in metabolic pathway

*inhibits glycogen synthesis

*promotes glycogen breakdown

kinase- phosphorylates

-glycogen phosphorylase- breaks down glycogen

glucose metabolism in RBC

limited capacity

-anaerobic metabolism (pyruvate to lactic acid)

-lactic acid leaves RBC and goes to liver

lack mitochondria

-can not do aerobic

oxidative branch of PPP

-protection of RBC

glucose metabolism in brain

can completely oxidize glucose

-aerobic metabolism

-TCA and ETS (greater than 90% of time)

completely dependent on glucose for energy

-even under times of starvation still requiring glucose (50%)

glucose metabolism in muscle

can completely of incompletely oxidize glucose

-anaerobic in times of high demand exercise (faster)

can store glucose as glycogen

-one of primary stores of glycogen

can also do PPP but does not do a lot

glucose metabolism in liver

can be completely oxidized

can store as glycogen

can convert to fatty acids or amino acids

can make glucose

(glycolysis or gluconeogenesis)

oxidative branch of PPP

glucose metabolism in adipocyte

glucose partially metabolized for fat synthesis

-get glucose from GLUT4 after meal

glycolysis

PPP

-lipid formation

*main reason adipocytes wants glucose is to STORE FAT

glycolysis

metabolism of glucose to pyruvate

-occurs in cytosol

-can proceed via anaerobic or aerobic metabolism

-generates ATP and NADH

-anaerobic glycolysis produces less ATP

phase 1 glycolysis

priming of glucose

-requires ATP

regulated steps:

-hexokinase or glucokinase

-phosphofructokinase-1

step 1 glycolysis

hexokinase or glucokinase

-glucose to glucose 6 phosphate

*have to put in ATP

REGULATED

step 2 glycolysis

phosphoglucose isomerase

-glucose 6 phosphate to fructose 6 phosphate

step 3 glycolysis

phosphofructokinase-1

-fructose 6 phosphate to fructose 1,6 bisphosphate

*have to put in ATP

REGULATED

step 4 glycolysis

aldolase

-splits fructose 1,6 bisphosphate into two molecules

step 5 glycolysis

triose phosphate isomerase

-splits dihydroxyacetone phosphate into glyceraldehyde 3 phosphate

step 6 glycolysis

glyceraldehyde 3 phosphate dehydrogenase

-glyceraldehyde 3 phosphate into 1,3 bisphosphglycerate

*produces NADH

REGULATED

step 7 glycolysis

phosphoglycerate kinase

-1,3 bisphosphoglycerate to 3-phosphoglycerate

*produces ATP

step 8 glycolysis

phosphoglycerate mutase

-3 phosphoglycerate into 2 phosphoglycerate

step 9 glycolysis

enolase

-takes off water

-2 phosphoglycerate into phosphenolpyurvate

step 10 glycolysis

pyruvate kinase

-phosphenolpyruvate into pyruvate

*produces ATP

REGULATED

glycolysis net reaction

IN: glucose + 2NAD+ + 2ADP + 2Pi

OUT: 2 pyruvate + 2 NADH + 2 ATP + 2 H2O

regulation of metabolic enzymes

modulation of allosteric enzymes

-do NOT bind to active site but rather inhibit or promote binding to active site

*NADH/NAD+ ratio (high- INHIBIT)

*energy status (high ATP INHIBIT)

*other modulators

FAST ACTING

hormonal regulation

*covalent modification (phosphorylation or dephosphorylation)

*induction or genetic regulation (hormone causes gene trancription and changes in gene expression)

LONG-TERM and SLOW

directional shifts in reversible reactions

*changes in reactant or product concentrations (feedback inhibition)

hexokinase

first step if in skeletal muscle

-phosphate traps molecule in skeletal muscle since it can not reverse reaction

allosteric regulation

-high concentrations of glucose 6 phosphate INHIBITS enzyme

-low km and low capacity- does not take much to activate

*negative feedback loop

RAPID conversion

glucokinase

first step if in liver

induction

-primarily changed by the entry of glucose into the cell

-high km and high capacity- only functional when high amounts of glucose entering the liver (after a meal)

-insulin PROMOTES activity and glucagon DECREASES but not the main activity

-glucose-6-phosphate very important in liver- can be used to make glycogen stores

GLUT2 function

need conversion of glucose into glucose-6-phosphate

-need constant stream of glucose into the liver after a meal

-if glucokinase was allosteric it would stop GLUT2 from functioning and would have more sugar in blood

diabetics and glucokinase

activity of glucokinase slows down or completely stops

-signal for insulin not working- part of the way we change induction

MODY

maturity onset of diabetes in the young

-develop severe resistance to insulin

-growth issues

hexokinase summary

-located in muscle, brain, and adipose tissue

-allosterically inhibited by glucose-6-phosphate

-low km: function at maximum velocity at fasting blood glucose concentrations

-not induced by insulin in normal individuals

-not induced by insulin in insulin resistant individuals

glucokinase summary

-located in liver and pancreas

-not inhibited by glucose-6-phosphate

-high km: function at maximum velocity only when glucose levels are high

-induced by insulin in normal individuals

-not induced by insulin in insulin resistant individuals

exercise and glycogen stores

depletes glycogen stores

-helps to promote glucokinase activity

-keeps blood sugars low

phosphofructokinase I

rate controlling enzyme of glycolysis

allosteric regulation

-energy status (ATP INHIBITS and ADP PROMOTES)

-fructose 2,6 bisphosphate (high concentrations PROMOTE enzyme)

-pH of the cell (low pH INHIBITS enzyme- lactic acid build up)

-Ca+2 concentration (influx of Ca+2 for muscle contractions PROMOTE enzyme)

hormonal status

-formation of fructose 2,6 bisphosphate

-induction (insulin will activate and glucagon will inhibit)

exercise

promotes glycolysis

ENERGETIC NEED!!!

-depletes glycogen stores in skeletal muscle

-Ca+2 influx promotes activity of PFK-1

-acts as a stress to release cortisol and glucagon (lower blood sugar and increase energy production or storage)

bifunctional enzyme

promotes or does not promote formation of fructose 1,6 bisphosphate

INSULIN (dephosphorylates ATP)

-activation of PFKII

-phosphate on fructose 6 phosphate to make fructose 2,6 bisphosphate

PROMOTES GLYCOLYSIS

GLUCAGON (phosphorylates ATP)

-activation of protein kinase I

-takes phosphate from fructose 2,6 bisphosphate

INHIBITS GLYCOLYSIS

*PFK-! allosterically stimulated by fructose 2,6 bisphosphate

pyruvate kinase

allosteric regulation

-energy status (ATP INHIBITS)

-product of PFK-I (fructose 1,6 bisphopshate PROMOTES)

-high levels of acetyl coA INHIBIT

-high alanine INHIBIT

hormonal status

-covalent modification (via dephosphorylation by insulin or phosphorylation by glucagon based on fasting conditions)

-induction (some gene expression)

acetyl coA and pyruvate kinase

produced by beta-oxidation which feeds into the TCA cycle

-fatty acid metabolism in fasting conditions

-need liver to be making glucose

pyruvate converted to acetyl coA (aerobic metabolism)

-TCA cycle not working- acetyl coA can build up

-used for fatty acid synthesis

HIGH ACETYL COA INDICATES FATTY ACID METABOLISM FOCUS- do not need to be breaking glucose

alanine and pyruvate kinase

high amount in liver after fasting- protein breakdown

-gluconeogenesis to make glucose

HIGH ALANINE INDICATES GLUCONEOGENESIS

- do not need to be breaking glucose

influence of NADH and NAD+ on glycolsis

*NADH is a product of glycolysis

high NADH

-pathway not needed

-inhibits glycolysis

high NAD+

-favors glucose oxidation

-now have substrate to be used for glycolysis

-promotes glycolysis

metabolism of pyruvate anaerobic

anaerobic

-generation of lactate via lactate dehydrogenase

-occurs in muscle and RBC

-generation of NAD+ without assistance

-can be recycled to liver to generate glucose- gluconeogenesis via the Cori Cycle

-build up of lactic acid will shut down the cycle

metabolism of pyruvate aerobic

aerobic

-production of acetyl coA from pyruvate

-requires mitochondria

-pyruvate dehydrogenase (another regulated complex)

-can also go to fatty acid production, ketones, or cholesterol if body does need directly need the energy

liver and RBC

Cori Cycle

-lactate from anaerobic metabolism in RBC goes to liver

-converted into glucose which can be taken up by RBC

overall regulation of glycolysis

glycogenesis summary

synthesis of glycogen (storage)

-FED state (after a meal)

-store in liver and skeletal muscle via GLUT4

-stimulated by insulin

importance:

-skeletal muscle- extra energy to break down for exercise

-liver- maintenance of blood sugar

glycogenolysis summary

breakdown of glycogen

-FASTED state

-stimulated by glucagon in liver

-stimulated by epinephrine in skeletal muscle

glycogen

-very large polymer of glucose molecules linked by a 1,4 and 1,6 bonds

-branches arise by a 1,6 bonds every 8-10th residue

-found in cytosol

glycogenesis

-process requires energy (anabolic)

-begins with phosphorylation of glucose by hexokinase or glucokinase

*add ATP to phosphorylate glucose-6-phosphate

--> either goes into glycolysis or glycogen synthesis

two enzymes:

glycogen synthase

-creates chains of glucose molecules with a 1,4 linkages

-UDP-glucose --> glycose (n+1) +UDP

glycogenin

-primer to start glycogen chain

amylo-a (1,4--> 1,6)-glucosyl transferase (branching enzyme)

-produces a 1,6 linkages

-only regulated by how much glucose is being added

fasting impact on glycogen stores

-ability to store glycogen becomes compromised

-only "24" hours of glycogen before metabolism begins to shift

depleting skeletal muscle glycogen

resistance training

-increasing muscle mass- now have more capacity to store glycogen

anaerobic

-depletes actual stores

-prevents extra glucose from going to fat

glycogenolysis

breakdown of glycogen to glucose (or glucose-6-phosphate) in respond to low blood glucose

*muscle can't convert to free glucose- goes into glycolysis

-not a reversal of synthetic reactions

-in humans, the store of liver glycogen lasts about 24 hours

glycogen phosphorylase

-cleaves a 1,4 linkages and forms glucose 1 phosphate

-G1P --> G6P

-can be converted to glucose in liver

oligo (a-1,4 --> a 1,4)-glucantransferase

-causes exposure of 1,6 branch point

amylo-a(1,6)-glucosidase (debranching enzyme)

-removal of a 1,6 branch points

-allows phosphorylase to proceed

debranching enzyme

bifunctional

-oligo-(a-1,4-->a,1,4)-glucantransferase

-amylo-a(1,6)-glucosidase

muscle glycogen synthgesis

decreased glycogen synthesis and storage in muscle in diabetics

*problem is GLUT4- can't get to membrane

skeletal muscle and dibaetics

becomes first tissue to become insulin resistant

-glucose goes somewhere else --> fat metabolism

key enzymes in glycogen metabolism regulation

glycogen phosphorylase

-glycogen breakdown

-forms G-1-P

-liver and muscle glycogen phosphorylated activated by phosphorylation (signaling through pKA)

*glucagon in liver and epinephrine in SM

glycogen synthase

-glycogen synthesis

-addition of glucose using UDP-glucose to glycogen chain

-activity inhibited by phorphorylation

*insulin

regulation of glycogen phorphorylase

covalent modification

-phosphorylation

allosteric control

-energy charge, glucose, G-6-P

*active via phosphorylation

a-active

b-inactive

in depth regulation of glycogen phosphorylation

PROMOTES ACTIVITY OF GLYCOGEN PHOSPHORYLASE A

-epinephrine or glucagon (pka does not directly do the action)

-phosphorylase kinase PHOSPHORYLATES ATP and adds P to activate glycogen phosphorylase a

*glycogen will be broken into glucose-1-phosphate

PROMOTES ACTIVITY OF GLYCOGEN PHOSPHORYLASE B

-insulin

-protein phosphatase 1 DEphosphorylates enzyme resulting in glycogen phosphorylase b

-also signals an enzyme called phosphodiesterase that breaks down cAMP

*glycogen will remain in storage form

kinase

phosphorylates a molecule

-adds a phosphate from ATP to an enzyme to alter its function

muscle regulation of glycogenolysis

allosteric regulation

-ATP will inhibit

-glucose-6-phosphate will inhibit

-AMP can promote active form of glycogen phosphorylase b

*extra AMP can override normal enzymatic pathwat

tissue regulation of glycogenolysis

allosteric regulation

-glucose will inhibit- overrides phosphorylation

regulation of glycogen synthase

*regulated primarily by reversible phosphorylation

DEPHOSPHORYLATION activates

calmodulin kinase

enzyme in the skeletal muscle

-activated by Ca+2

-exercising releases

-can promote phosphorylation and activate glycogen synthase b (inactive form)

galactose summary

dietary sources:

-dairy products

-some fruits and. vegetables

intestinal absorption

-requires SGLT1 and GLUT2

liver metabolism

-galactokinase (phosphorylates)

inability to metabolize

-galactosemia- build up of byproducts which can result in organ damage

-test for day 2 after birth (can NOT consume breastmilk)

galactose metabolism

LIVER

galactose

galactose-1-P

eventually broken down into glucose-6-P

*end result is the same as glucose

can be fed into:

-glycogen production

-glycolysis

-PPP

fructose

dietary sources:

-fruits

-sweeteners (sucrose 50%, honey 40% , HFCS, added sugars)

**issue is with sweeteners- easy to overdo consumption

-fructose is 10-15% of caloric intake

-linked to some disease states due to metabolic shifts that occur

high fructose corn syrup vs table sugar

sugar

-derived from sugar cane

-fluctuates based on imports and exports

high fructose corn syrup

-source of fructose

-cheaper option

-corn is pure starch (100% glucose)

-make corn syrup and add enzymes that convert some of the glucose into fructose

*thought to be absorbed more quickly

fruit and fructose

fructose content varies

-may suggest lower fructose options for certain patients

high

-dried and dehydrated fruits

-apples

-grapes

-watermelon

low

-berries

*less likely to be involved in disease as added sugars

-has beneficial constituents such as flavanols, fiber, antioxidants

fructose metabolism

fructokinase

-adds a phosphate in the liver

*most fructose is being converted to glucose in the intestines

-hardly see any fructose coming out of liver in systemic circulation

PROBLEM IS WITH EXCESS DOSES

-the liver will not convert all of it to glucose

-more fructose

LIVER

fructose

fructose-6-P

glyceraldehyde + dihydroxyacetone phosphate

glyceraldehyde-3-phosphate

*bypasses PFK-1 but can eventually feed into the glycolysis pathwat

fructose malabsorption

highly variable in children and adults

-about 34% of adults (higher with GI disorders)

-mechanism unknown

study found that lean children has higher fructose malabsorption

fatty liver disease

greater than 5% of the liver is fat

stages:

-fatty

-steatohepatitis (fibrosis)

-cirrhosis (NOT REVERSIBLE)

-cancer

fructose metabolism and fatty liver disease

-bypasses regulation of PFK-1

-very rapid metabolism

-results in drop in ATP and P1- ATP depletion (fructokinase)

-formation of uric acid due to increased fructose coming into the liver (AMP deaminase converts AMP to uric acid)

uric acid and fatty liver

shown to

-stimulate lipogenesis

-inhibit fatty acid oxidation

-stimulate gluconeogenesis

other risk factors for fatty liver

-fructose combined with a high fat diet produces more severe fatty liver

-alcohol with fructose

-high GI diet can induce endogenous fructose production (polyol pathway makes fructose from glucose)

-high salt diet

TCA cycle

oxidation of acetyl coA to CO2 and H2O

-aerobic- requires the mitochondria

also produces:

-NADH

-FADH2

pyruvate dehydrogenase

pyruvate to acetyl coA

-produces NADH

associated with inner mitochondrial membrane

regulated:

-covalent modification (phosphorylation and dephosophorylation)

-NADH/NAD+

-ATP/ADP

-acetyl coA

activates:

-dephosphorylation (insulin)

-high NAD+

-high ADP

inhibits:

-phosphorylation

-acetyl coA

TCA functions

*produces most of CO2 made in humans

*source of reducing equivalents that drive respiratory chain to produce ATP

*converts excess energy and intermediates into fatty acid synthesis (citrate build-up)

*provides precursors used in synthesis of proteins and nucleic acids

*regulation of other metabolic pathways

TCA phases

-acetyl coA production

-acetyl coA oxidation

-electron transfer

electron transport chain

regulation of TCA cycle

flux of ETC

-state of ATP

-reduction state of NAD+

citrate synthase

oxaloacetate and acetyl coA to citrate

product and substrate concentrations

-low substrate inhibits

-a lot of citrate inhibits

allosteric

-ATP inhibits

isocitrate dehydrogenase

isocitrate to a-ketoglutarate

allosteric

-NADH and ATP inhibit

-Ca+2 activates (more ATP for the muscles)

a-ketoglutarate dehydrogenase

a-ketoglutarate to succinyl coA

allosteric

-NADH inhibits

-Ca promotes in skeletal muscle

pyruvate carboxylase

pyruvate to oxaloacetate under fasting conditions

increase in acetyl coA

-regulated positively

replenishes OAA to drive TCA

*anapleurotic reaction

gluconeogenesis

production of glucose from nonhexose precursors

occurs all the time at a low level but increased under fasting conditions

*90% occurs in liver and 10% in kidney

-requires energy

-maintains blood glucose

what drives gluconeogenesis

ATP comes from the breakdown of fat

-switch from carb to lipid metabolism

ENERGY FROM FAT USED TO DRIVE GLUCONEOGENESIS

precursors for gluconeogenesis

-lactate

-glycerol

-gluconeogenic amino acids (all except lysine and leucine)

three irreversible reactions in glycolysis bypasses in gluconeogenesis

hexokinase

-glucose 6-phosphatase

PFK-1

-fructose 1,6-bisphosphatase

pyruvate kinase

-PEPCK

-pyruvate carboxylase

lactate

lactate dehydrogenase REVERSIBLE

-liver puts into pathway to make more glucose

-skeletal muscle and RBC both naturally produce a lot (produces NAD+)

*precursor for gluconeogenesis

alcohol and hypoglycemia

generates excess NADH which inhibits gluconeogenesis

amino acids

alanine aminotransferase

-alanine into pyruvate

signaled by increased protein breakdown due to fasting (takes about 24 hours to start breakdown- cortisol release)

*precursor for gluconeogenesis

glycerol

glycerol kinase

-glycerol to glycerol 3-phosphate

glycerol 3-phosphate dehydrogenase

-glycerol 3 phosphate into dihydroxyacetone phosphate

(part of gluconeogenesisi)

-glycerol is from fat breakdown

-NADH produced

*precursor for gluconeogenesis

three sites of regulation for gluconeogenesis

-glucose 6 phosphatase

-fructose 1,6 phosphatase

-pyruvate carboxylase and PEPCK

pyruvate carboxylase regulation

acetyl coA promotes

-anapleurotic

-source of OAA for TCA and carbon source for gluconeogenesis

PEPCK regulation

amount of this enzyme

-liver controls expression based on fed or fasted state

fructose 1,6 biphosphatase regulation

OPPOSITE OF PFK-1

activated by

-ATP

-citrate

inhibited by:

-fructose 2,6 bisphosphate

-AMP and ADP

glucose 6 phosphatase

*do NOT have in skeletal muscle

activated by:

-glucose-6-phosphate

-glucagon

what effect does diabetes have on gluconeogenesis

insulin resistance leads to

-increased fat metabolism

-increased protein breakdown

-increased levels of glucagon

**increased gluconeogenesis- overproducing glucose

pentose phosphate pathway

production of 5 carbon monosaccharides and NADPH

-5 carbon sugars (ribose-5-phosphate) used for nucleotide and nucleic acid formation

-NADPH for biosynthetic reactions

*can take glucose-6-phosphate and shunt it into NADPH and 5C sugars

-no hormonal regulation

NADPH reactions

-fatty acid synthesis

-production of steroids

-reduction of glutathione in RBC

*used as a protective mechanism against oxidative stress- every cell needs

PPP occurs

more in the fed state

-synthesis of lipids

*utilizing extra carbons

REGULATED BY TISSUE NEED NOT HORMONES