Biochem 4

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IndigestibleFiber

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Cellulose

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a-amylase, cleaves what kind of bonds

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•cleaves a-1,4 glycosidicbonds

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•no carbohydrate digestion in

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stomach

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Action of salivary and pancreatic amylases

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Causes random cleavage which lead to limit dextrins

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Four glycoproteins/glycosidases of the small intestine

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A.Glucoamylase

B.Sucrase-isomaltase

C.Trehalase

D.Lactase-glucosylceramidase

Responsible for converting disaccharides and oligosaccharides to monosaccharides

Attached to brush border

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Glucoamylase

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Exoglucosidase

Specific for a-1,4 glycosidic bonds

Cut at the nonreducing end to form mono

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Sucrase-isomaltase

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a-1,6 bonds cleaved by isomaltase-maltase activity

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Trehalase

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cleavestrehalose, (found in mushrooms,honey and shrimp)

Trehalasedeficiency has symptoms similar to a-amanitinpoisoning

cleaves a-1,1 bond

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b-glycosidase complex (Lactase)

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hydrolyzes b-1,4 bond

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Starch broken down with what and to what products

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Broken down via salivary and pancreatic a amylase

Maltose

Limit dextrins

trisacchardies (maltotriose)

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Lactose intolerance is the inability to convert lactose into

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glucose and galactose

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Rate of Absorption of Sugars

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glycemic index

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Low glycemic index

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Foods are digested more slowly

Fewer spikes in blood sugar

Better for diabetics

ex starch

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High glycemic index

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Foods are digested quickly

See more spikes in blood sugar

Worse for diabetics

ex candy

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Glucose taken up by different tissues by different

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tissue-specific transporters

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Glucose Uptake in the Intestine

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Glucose is polar, so cant cross membrane

Facilitateddiffusion

Na+-dependent facilitated transpor

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GLUT 4 transporter

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Found in

Adipose

Skeletal

Heart

Insulin sensitive transporter

Will increase the number of glucose transporters at the surface

High affinity

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Blood-brain barrier has specific transporters for

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GLucose

Non-neural, glucose can diffuse

Neural, glucose has high affinity transporters

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Structure of Glycogen

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Only one anomeric carbon permolecule of glycogen

Maybe simultaneously degraded from all nonreducing ends

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Structure of Glycogen 2

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Have the straight long chains via the a 1,4

Able to branch via the a 1,6

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Role of Glycogen

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Found in liver

Primarysource of glucose for maintenance of bloodglucose

glycogen broken down to G1P and G6P

Have to remove P, so glucose can leave

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Futile cycling

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No futile cycling in cells

Body knows when it needs to break down and when it needs to build up, relative to gylcogen

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Common Theme forMetabolism

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•Synthesis requires energy

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Glucose enters cell and is converted to G6P by

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glucokinase

Traps glucose in cell

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Glucose 1-phosphate

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G1Pis precursor of glycogen synthesis (and product of glycogendegradation)

Producedby phosphoglucomutase(reversible)

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UDP-G intermediate only used in

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biosynthetic pathway

not used in degradation

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Branching allows for

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increased sites for synthesis and degradation and enhances solubility

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What is responsible for glycogen synthesis

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Glycogen synthase

which is regulated

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Branching enzyme in glycogen

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amylo-4,6-transferase

reattaches the a 1 6 bond

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Degradation of Glycogen uses 2 enzymes

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Glycogen phosphorylase

Debrancher enzyme

transferase

amylo-1,6-glucosidase

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Glycogen Storage disease 1

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Enzyme affected glucose 6 phosphatase

(Von Gierkes)

Liver

Liver only organ that removes the P. cant release glucose while fasting Can breakdown gylycogen but cant put it into blood bc ofthe p still attached to glucose

More severe bc cant get any glucose out during fast

Will lead to enlarged liver and kidneys

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Glycogen Storage disease 2

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Muscle gylcogen phosphorylase (McArdies)

Skeletal muscle

Differentenzyme in the skeletal. Only seen in skeletal muscle, cannotbreak down glycogen

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Glycogen Storage disease 3

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Liver glycogen phosphorlase (Hers)

Liver

Can't break down glycogen in the liver

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Case study

Atwo-year-old girl presents with a mildlyenlarged liver, history of hypoglycemia on several occasions and growth belowthe third percentile for her age.

What glycogen storage disease?

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Hers disease

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Regulation ofGlycogen Synthesis/Degradation

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Fasted state

•Glycogen phosphorylase a (active) isactivated by phosphorylation•Glycogen synthase D (b) is inactivated byphosphorylation

GPand GS are simultaneously regulated by covalent modification

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Glucagon acts via

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cAMP – secondmessenger

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Regulation of Glycogen Degradation: role of PKA

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cAMPbinds regulatory subunits of protein kinase A (PKA)

PKA phosphorylates phosphorylase kinasewhich phosphorylates glycogen phosphorylase b convertingit to glycogen phosphorylase a (active)

Glucose released from liver to maintain blood sugar levels

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Inhibition of Glycogen Synthesis

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PKAphosphorylates ~10 different kinases which phosphorylate glycogen synthaseon multiple serine residues

When phosphorylate glyocgen synthase

becomes inactive

Glycogensynthesis is inhibited

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Hepatic protein-phosphatase-1

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removes phosphates from phosphorylasekinase, glycogen phosphorylase and glycogen synthase

activated by insulin

start making glycogen

happens fed state

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Principal regulator for blood glucose

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•Insulin is principal regulator

Highcarbohydrate meal

•stimulates insulinrelease

•suppresses glucagon release

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Effects ofEpinephrine on Glycogen Metabolism

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Epinephrineenhances the effects of glucagon in liver

IP3 stimulates release of Ca2+ from ER

IP3 and Ca2+ are secondary messengers

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Glycogen Metabolismin Skeletal Muscle

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NoGlucose-6 phosphatase in muscle

•Glucoseisnot inhibitoryin muscle glycogenolysis

•Glycogenisinhibitory in glycogen synthesis (less stored)

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Glycogen synthesis summary

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Synthesis

G to G-6-P

1.G-6-P to G-1-P

2.G-1-P to UDP-G

3.UDP-G to Glycogen

4.Branching

Stimulatedby insulin.s

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Glycogen degradation summary

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Degradation

1.Branched-Glycogen to Limitdextrins & G-1-P

2.Limitdextrins to G-1-P

3.G-1-P to G-6-P

G-6-P to G or F-6-P

Stimulatedby glucagon and/or epi inthe liverStimulatedby AMP, Ca++and/or epi inthe muscle.

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What organ releases insulin or glucagon

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Pancreas

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Insulin and InsulinCounterregulatory Hormones

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Insulinpromotes storage of glucose as TG or glycogen in muscle and adipose tissue

Glucagon and epinephrine promote glucosemobilization via glycogenolysis and gluconeogenesis

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MetabolicHomeostasis

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Excessglucose, lipid and amino acids must be removed from blood

Excesssugar and amino acids would cause a hyper-osmotic state

Excessglucose can cause non-enzymatic glycosylation of proteins

Excesslipid can cause atherosclerosis

Itall comes down to a balancing act!

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Inaddition to glucagon, stress hormones regulatefuel utilization

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epinephrine

cortisol

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Glucagon acts mainly on

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liver and adipose tissue(not muscle – no receptors)

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Glucagon released from what cells and in response to what

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alpha-cellsin response to reduction of glucose and/or

rise in insulin in blood bathing a-cells

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Glucagonrelease does not alter muscle metabolism because

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Musclecells lack the glucagon receptor

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Insulin synthesized as

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preprohormone

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In proinsulin, what is cleaved

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C-peptide

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Significance of C-peptide

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Can tell you how much insulin has been made

Cpeptide also secreted into the blood as well as insulin com

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Insulin released from what cells

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beta cells in pancreas

amount of insulin released is proportional to how much is needed

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Synthesis ofGlucagon

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Preproglucagon

3to 5 minute half life

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Regulators ofGlucagon Release

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Mainlyinhibited by glucose and insulin inblood

Stimulatedby AAs

Highprotein/low carb meal stimulate glucagon release

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Regulators of Insulin Release

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Blood glucose over 80

Also To a lesser extent, certain amino acids,gastric inhibitory peptide and glucagon-like peptide

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Effects of HighProtein Meal

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•Stimulate glucagon release

•Stimulate insulin releaseto lesser extent

•Gluconeogenesisenhanced

•Reducedglycogen and TG synthesis

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Diabetes Mellitus symptoms

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Hyperglycemia

Polyuria

Polydipsia (thirst)

Weightloss

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Diabetes mellitus can be detected by

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–easilydetected on hemoglobin (HbA1c)

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DM type 1

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–Autoimmunedestruction of b-cells

–Almostundetectable [insulin] in blood

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DM type 2

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•(insulinresistant)

–Skeletalmuscle and liver “resist” action of insulin

–Insulinlevel can be normal in these patients

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DM MODY

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•MODY (maturityonset diabetes of the young)

–decreasedglucokinaseactivity

–requires↑[glucose] to cause ↑ [ATP]

–thereforeinsulin release only at ↑ [glucose]

MODY-slow

Don’t get sudden increase in ATPtherefore insulin release only at ↑ [glucose]

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Sulfonylureas

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•blockK+ channels–increaseinsulin secretion

Sulfonylureas only works on mody anddm2

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Apatient with type 1 diabetes mellitus takes an insulin injection before eatingdinner but then gets distracted and does not eat. Approximately 3 hours later, the patientbecomes shaky, sweaty and confused. Thesymptoms have occurred because of which of the following?

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Lowblood glucose levels

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Glucagon

Secondmessenger system

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Trimeric G

cAMP

PKA

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Insulin

Second messenger system

Back 68

TyrosineKinase

PIP3

PKB

Front 69

Fructose synthesized in the body from

Back 69

glucose via the polyol pathway

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Fructose in eye can cause

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cataract formation

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Fructose metabolized by

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Conversion to intermediates of glycolysis

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Fructose enters the cell via

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GLUT 5 transporters

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Fructose yields intermediates from glycolysis

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dihydroxyacetone-P and glyceraldehyde-3-P

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Fructose Aldolase B

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B cleaves fructose 1-P

Aldolase B is rate-limiting enzymeof fructose metabolism

notrate-limiting for glycolysis

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Aldolase B deficiency

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Accumulation of Fructose-1-P.

Inhibits the breakdown of glycogen and also gluconeogenesis.

Leads to Hypoglycemia,high lactate, low ATP

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Essentialfructosuria

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deficiencyin fructose kinase

Benign

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HereditaryFructose Intolerance (HFI)

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–deficiencyin aldolase B

Fatal

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Whyis essential fructosuriaa benign genetic disorder, while hereditary fructose intolerance can be fatal?

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Just cant breakdown fructose for benign, fructose not toxic, leave inthe urine

F1pdoes buildup, cant break down glycogen cant restore blood glucoselevels. Low ATP, high lactic acid

Dangerousto fast w/ this condition

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The Polyol Pathway

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Convertsglucose to fructose

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2 steps of polyol pathway

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Reduction of C1 by aldose reductase

formssugar alcohols (e.g., sorbitol)

Oxidation of C2 by sorbitoldehydrogenase

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This cell uses frucotse

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Sperm use fructose

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Eye complications with polyol pathway

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Indiabetes when glucoseis high, this reaction is pushed forward in the eye. The conversion to fructose is slow and theincreased concentration of sorbitolleads to increased intraocular pressure.

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High sorbitol in muscle and nerves

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Accumulation of sorbitol inmuscle and nerve may contribute to peripheral neuropathy in diabetics

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Eye complications with polyol pathway

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Indiabetes when galactoseis high, this reaction is pushed forward in the eye. The conversion to fructose is slow and theincreased concentration of galactitolleads to increased intraocular pressure.

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Pentose PhosphatePathway

Back 85

•Generates NADPHfor reducing equivalents and ribose 5-P fornucleotide biosynthesis

•Onlysource of NADPH for RBCs

•Pentose intermediates are reversiblyinterconverted to intermediates of glycolysis

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Pentose Phosphate Pathway

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Produces 2 NADPH per glucose

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4 key enzymes in nonoxidative PPP

Back 87

isomerase,

epimerase,

transketolase

transaldolase

Ribulose5 phosphate is isomerized to ribose 5-phosphate (R5P)

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Transketolase

Back 88

transfers a twocarbon unit

Transketolaserequires thiamine

Thiaminedeficiency is common in alcoholics

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Transaldolase

Back 89

transfers a threecarbon unit

Finalnet result of nonoxidative PPP from 3 mol of ribulose 5-P: 2 mol fructose 6-P and 1 molof glyceraldehyde 3-P

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Pentose PhosphatePathway end products

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Overallreaction:

interconversion of 3 G6P into 6 NADPH,

3CO2,

2 fructose 6-P,

1 glyceraldehyde3-P

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PPP is important is what cell types

Back 91

all cell types

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Regulation of PPP

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Glucose-6-Pdehydrogenase

Allosteric Feedbackinhibition by NADPH

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Favism

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Fava beans can cause produce H2O2 which can cause hemolytic anemia

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DefectiveG6PDH

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•Resultsin enzyme with unstable structure

–Patientwith 10% of normal activity

–Enoughto generate NADPH under normal conditions

•Newlymade RBCs have normal G6PD activity

–Patientsrecover quickly (~8 days)

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Gluconeogenesis

Back 95

•Glucose is synthesized from noncarbohydrateprecursors

•Stimulated by glucagon

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Gluconeogenesis differs fromglycolysis at

Back 96

3 key steps which are regulated byglucagon and insulin

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Precursors forGluconeogenesis

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Carbon sources are lactate(from anaerobic glycolysis in RBCs and muscle), aminoacids from muscle pools, alanine and glycerol fromadipose tissue

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Alanine gets converted to

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Pyruvate

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ATP Yield for glycolysis

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yeilds 2 ATP

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ATP Cost for gluconeogenesis

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costs 6 ATP

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Regulation to prevent futile cycling b/w glycolysis ad gluconeogensis

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This regulation occurs through phosphorylation, gene transcription andallosteric interactions at several steps along both pathways.

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Hyperglycemialeads to

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osmoticdehydration of tissuescanlead to hyperosmolar coma from brain dehydration

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Hypoglycemialeads to

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depletionof ATP:

brain – dizziness, drowsiness,comablood– hemolysis due to loss of integrity of membranes

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Insulin affects during glycolysis

Back 104

glucose to G6P via glucokinase

increased

F6P to F1,6P via phosphofructokinase-1 (most important control point)

increased

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Glucagon affect during gluconeogenesis

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F1,6P to F6P via fructose 1,6 bisphosphatase

(most important control point)

G6P to Glucose via glucose 6 phosphatase