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Human diseases of carbohydrate metabolism. Inherited enzyme deficiencies. Mutations that change enzyme function or abolish enzyme activity. Most are recessive since only one functional copy of gene is sufficient for needed activity. Diabetes. Lactose intolerance. Galactosemia.

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slide1

Human diseases of carbohydrate metabolism

Inherited enzyme deficiencies

Mutations that change enzyme function or abolish enzyme activity

Most are recessive since only one functional copy of gene is sufficient

for needed activity

Diabetes

Lactose intolerance

Galactosemia

Glycogen storage disease

slide2

Monosaccharides - Aldoses

# Isomers = 2n where

n = # of chiral carbons

Enantiomer

Distant chiral C

From most oxidized

Epimers – differ in configuration at only one chiral carbon

Not all made in nature

slide3

Monosaccharides - Ketoses

# Isomers = 2n where

n = # of chiral carbons

slide4

Cyclization - aldohexose

  • Draw most oxidized carbon (C1 aldose and C2 ketose) on right and number C clockwise
  • In ring most oxidizes carbon new chiral center (anomeric C)
  • Transfer information from Fisher projections
    • -OH on right then down in Haworth
    • -OH on left then up in Haworth
    • Bulky substituent on highest numbered carbon points up

Anomers

rapid equilibrium

slide5

Cyclization - aldopentose

Equilibrium

Anomeric C

Hemiacetal

Haworth

projection

Anomers

slide6

Glycolysis: Steps 2 and 3

Opens the chain

during the rxn

PFK-1

CH2OH

OH

utilizes 100% -anomer

Stereospecific: uses -Glc; produces 100% -D-fructose-6-phosphate

36% -fructose 64% -fructose

slide7

Glycoside Bonds – Disaccharides

No open chain equil

Hemiacetals -a reactive carbonyl that can be oxidized.

reducing

non-reducing

b anomer: refers to free C1 OH

non-reducing sugar

slide8

Glycoside Bonds – Disaccharides

epimer

Most abundant disacc. in nature (plants)

slide9
Humans don’t have b-glucosidases

Microbe that live in ruminants do

Polysaccharides –Structure

Amylose

  • Cellulose
    • b-(1-4) linkage

180 deg rotation

300- 15,000 Glc residues

Rigid extended conformation

H-bonding

Forms bundles or fibrils

Plant cell walls, stems

and branches

termites

slide10
Plant starch –

mixture of amylose and amylopectin

Animals glycogen

Polysaccharides –Glucose Storage

  • Homoglycans- one type of monosaccharide

Amylose

  • 100-1000 glucose residues (maltose units)

Amylopectin

and

Glycogen

Amylopectin:

branch every 25 residues

Glycogen:

branch every 8-12 residues

10% mass of liver

  • No template (ie no gene)
slide11
Humans digest starch via two enzymes:

α -amylase - endoglycosidase of α-(1-4) linkages (random)

debranching enzyme

(cleaves limit dextrans)

Higher plants have

β- amylase exoglycosidase of α- (1-4) linkages, releasing the disaccharide maltose

Polysaccharides -Starch Degradation

Know how starch is broken down !

Single reducing end

multiple non-reducing end

slide12

Glycogen Metabolism

Synthesis:

Different enzymes for

syn and degradation

Driven by PPi hydrolysis

Major regulatory step

slide13

Key regulation

by phosphorylation

(hormonally regulated)

Pre-existing

Glycogenin primer

Amylo-(1,4 1,6)-transglycolase catalyzes the branch point. (Alpha 1-6 link)

slide14

Degradation:

Two subunits, two catalytic sites, allosteric sites.

AMP- activator; ATP & Glc-6-P – inhibitor.

Phosphorylation: active (phosphorylase a).

Dephosphorylated: less active (phosphorylase b).

Phosphorolysis rxn.

Generates phosph-sugar not free glc

Primary regulation

slide15

Branching inc speed of

syn and degradation

phosphorolytic

Reg by ATP and G-6-P

Sequential removal of Glc

From non-reducing end

Stops 4 Glc from branch pt

Primarily by phosphorylation

Consequences of branch

Reducing vs non-reducing ends

solubility

Rate of syn/degradation

Energy yield from glycogen

Higher than from glc

slide16

Human diseases of carbohydrate metabolism

Inherited enzyme deficiencies

Mutations that change enzyme function or abolish enzyme activity

Most are recessive since only one functional copy of gene is sufficient

for needed activity

Diabetes

Lactose intolerance

Galactosemia

Glycogen storage disease

slide17

α -amylase

lactase

Glc + Gal

slide18

Absorbed from intestine

Major source of energy for nursing animals

In liver

20% of caloric intake of infants

Glc-6-P

slide20

Glucose metabolism

lactase

Glc + Gal

Glc

glucogen

Glc

glucogen

Glc 1-P

Glc 6-P

Fruc 6-P

Fruc 1,6-P

slide21

X

Absorbed from intestine

Major source of energy for nursing animals

In liver

20% of caloric intake of infants

X

Two inherited metabolic errors

Glc-6-P

Hypolactasia (lactose intolerance)

Galactosemia

slide22

Lactose Intolerance

X

Single gene defect

Normal decrease in enzyme by 6 yrs old

10% of original activity

(Northern Europeans are lactase producing adults)

Mutation in chromosome 2

Lactase deficient people:

Lactose passes intact into colon

bacteria in colon ferment to lactic acid, methane and H gas

Bloated/ gas and diarrhea

Can also hinder absorption of other nutrients

Avoid dietary lactose

Take enzyme substitute

slide23

Galactosemia

X

Galactose 1-P accumulates in liver cells (high galactose in blood and urine)

Decrease liver function and cataracts death

CNS damage and mental retardation (even if avoid milk)

cataracts

Cataracts (clouding) due to high galactose in eye. Converted to galactol allowing

diffusion of water into eye

slide24

Glucose metabolism

glucogen

Glc

Glc

glucogen

Glc 1-P

Glc 6-P

Fruc 6-P

Fruc 1,6-P

slide25

Glycolysis and Cancer

Defined: Glucose is converted anaerobically to the three carbon acid pyruvate

Net Reaction:

Glucose + 2 ADP + 2 NAD+ + 2 Pi

2 Pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O

Generates ATP at higher rate than Oxid Phosp

Oxidative phosphorylation: allows more energy extracted from Glc

Otto Warburg-cancer cells utilize glycolysis even in presence of O2

Aerobic glycolysis: Warburg effect

Initial stages of tumor growth vessels grow at slower rate:

cells deprived of O2

Cells switch to reliance to glycolysis

Max energy when pyruvate from glycolysis enters Citric Acid Cycle

slide26

Glycolysis and Cancer

Continue to rely of Glycolysis even when O2 restored to tumor

Can visualize tumors based on inc sugar uptake (PET scan)

Treatment?? Blocking lactose dehydrogenase (block NAD regeneration turn off Glycolysis)

slide27

Glucose

ATP

Phosphorylation

Hexokinase

ADP

Glucose-6-phosphate

Know key reg steps!

Isomerization

Glucose-6-phosphate isomerase

Fructose-6-phosphate

ATP

Phosphorylation

Phosphofructokinase-1

ADP

Fructose-1,6-bisphosphate

Cleavage

Aldolase

Dihydroxyacetone phosphate

Isomerization

Trios phosphate isomerase

Glyceraldehyde-3-phosphate

Glyceraldehyde-3-phosphate

NAD+ + Pi

Oxidation and Phosphorylation

Glyceraldehyde-3-phosphate dehydrogenase

NAD+ + Pi

NADH + H+

NADH + H+

1,3-bisphosphoglycerate

1,3-bisphosphoglycerate

ADP

Substrate Level Phosphorylation

ADP

Phosphoglycerate kinase

ATP

ATP

3-phosphoglycerate

3-phosphoglycerate

Phosphoglycerate mutase

Rearrangement

2-phosphoglycerate

2-phosphoglycerate

Enolase

H2O

Dehydration

H2O

phosphoenolpyruvate

phosphoenolpyruvate

ADP

ADP

Substrate Level Phosphorylation

ATP

Pyruvate kinase

ATP

pyruvate

pyruvate

slide28

Enzymatic Regulation of Glycolysis

Not moving forward, stop converting ATP

Cellular rxns are converting ATP and ADP, make more ATP

You’ve committed!

Bi-phosphated furanoses, keep pathway moving

CAC intermediates, slow down, there is already adequate

supply of energy

slide29

Glycolysis: Hexokinase Isozymes

Hexokinases (I-III)

-regulated negatively by Glc-6-P

-if later steps slow down, Glc-6P builds up

Glucokinase (IV) in Liver

-regulated negatively by Fru-6-P

-pulls glucose out of bloodstream until equil

-liver can produce more Glc-6-P

-converts Glucose to Glycogen storage

I-III

IV

Isozymes

Different inhibition profiles

Location, Km

Control point

Glc

Glc

glucogen

Glc 1-P

Glc 6-P

Can’t leave the cell with negative charge

Fruc 6-P

Fruc 1,6-P

slide30

in Liver

Hormones Involved

High blood [Glc], insulin released

Low blood [Glc], glucagon released

Insulin Dependent Uptake

Muscle

Adipose

Major function of liver: maintain constant level of Glc in blood

Release Glc (from glycogen) during muscle activity and between meals

slide31

Glucose 6-phosphatase

Most cases Glc-6-P is end product---used in other pathways

- glycogen, starch, pentose, hexose synthesis

Enzyme only found in liver, kidney, small intestines

Bound to ER with active site towards lumen

Hydrolysis of phosphate irreversibly forms glucose

Secretory pathway exports to blood stream for other tissues

slide32

Body does not transfer pyruvate

Lactate- produced in RBC and Muscle

Lactate to pyruvate in liver

Cori cycle

Major function of liver: maintain constant level of Glc in blood

Release Glc during muscle activity and between meals

Breakdown of glycogen to Glc 6-P (does not leave the cell)

Liver contains glc 6-phoshatase enzyme

Glc not major fuel in liver

slide33

Regulation of Phosphofructokinase-1

Large oligomeric enzyme

bacteria/mammals - tetramer

yeast - octamer

ATP - product of pathway

- allosteric inhibitor

AMP - allosteric activator

- relieves inhibition by ATP

Citrate - feedback inhibitor

- regulates supply of pyruvate

- links Glycolysis and CAC

Fru-2,6-bisphosphate

- strong activator

- produced by PFK-2 when excess

fru-6-phosphate

- indirect means of substrate

stimulation or feed forward

activation

slide34

Regulation of Pyruvate Kinase

+ F 1,6 BP

Inactivation by covalent modification

-blood [Glc] drops, glucagon released

-liver protein kinase A (PKA) turned on

-PKA phosphorylates pyruvate kinase

Allosteric (feed-forward) activation

Fructose-1,6-bisphosphate

-allosterically activates

-produced in step three

-links control steps together

Allosteric inhibition by ATP

-product of pathway and CAC

Low blood [Glc]

High blood [Glc]

slide35

Regulation of Glycogen Metabolism

Hormonal Regulation:

Fed state

fasting

Via cAMP

Via PIP3

Insulin: secreted by pancreas when Glc high inc rate of transport into cell and glycogen syn

GLUT4

Glucagon: secreted when Glc low

Epi: released by adrenal gland in response to neural signal (flight or flight)

Sudden energy response

slide36

Gluconeogenesis

Liver

glycogen

PPP

- 3 places differ- control points in glycolysis

- 4 new enzymes

ATP energy, NADH reducing equivalents consumed

Glc also syn from pyruvate

(lactate and amino acids)

Liver/kidney

Glc needed in brain/muscle

slide37

Gluconeogenesis: Regulation

Modulate one enzyme and affect 2 opposing pathways

Sensitive regulatory point

Low [Glc]: glucagon increases protein kinase A (activates Fru-2,6-bisP phosphatase) lowering [Fru-2,6-bisP].

Activate Glc syn

and

Loss of glycolysis stim

slide38

Regulation of Glycogen Metabolism

Hormonal Regulation:

Fed state

fasting

Via cAMP

Via PIP3

Insulin: secreted by pancreas when Glc high inc rate of transport into cell and glycogen syn

GLUT4

Glucagon: secreted when Glc low

Epi: released by adrenal gland in response to neural signal (flight or flight)

Sudden energy response

slide39

Intracellular Regulation

of Glycogen Metabolism by

Interconvertible Enzymes:

Low glc activate kinase and breakdown

Simultaneous

effect

Low [Glc]

slide41

Human diseases of carbohydrate metabolism

Inherited enzyme deficiencies

Mutations that change enzyme function or abolish enzyme activity

Most are recessive since only one functional copy of gene is sufficient

for needed activity

Diabetes

Lactose intolerance

Galactosemia

Understand how enzyme deficiency

leads to accumulation of glycogen

Glycogen storage disease

Other symptoms

Treatment, if any

slide42

Glycogen storage disease

glucogen

Glc

X

V

II, III, VI

X

X

Glc

glucogen

Glc 1-P

Glc 6-P

I

IV

Fruc 6-P

All defects lead to

glycogen accumulation

X

VII

Fruc 1,6-P

I

Glucose-6-Phosphatase in liver (von Gierk’s disease):

hypoglycemia (low blood glc) when fasting

Liver enlargement

IV

Branching enzyme in organs (liver) (Andersen’t disease)

Liver dysfunction and early death

V

Glycogen phosphorylase in muscle (McArdle’s disease)

Muscle cramps with exercise

VII

Phosphofructokinase in muscle

Glycogen accumulation and

Inability to exercise

slide43

Glycogen storage disease

Type I:

Glucose-6-Phosphatase deficiency in liver (von Gierk’s disease):

Glc not released into blood

No response to Epinephrine or Glucagon

hypoglycemia (low blood glc) between meals

infant in convulsions

Large amounts of glycogen in liver (G-6-P inhibits breakdown)

Liver enlargement

Glc-6-P increases glycolysis inc lactate/pyruvate in blood

(Lactic acidosis)

Delayed puberty, short stature

Continuous feedings of cornstarch (intragastric feeding)

Drug induced inhibition of Glc uptake by liver

Surgical transplant of portal vein (normally intestine-liver)

Glc to peripheral tissues before liver

slide44

Glycogen storage disease

Type IV:

Most severe disease

Branching enzyme deficiency in organs (liver) (Andersen’s disease)

Accumulate abnormal glycogen

Reduced solubility of glycogen

Foreign body immune response??

Liver dysfunction

Failure to thrive----- death 2-5 yrs old

slide45

Glycogen storage disease

Type V:

Glycogen phosphorylase deficiency in muscle (McArdle’s disease)

No breakdown of glycogen

Exercise indices muscle cramps otherwise normal

Effective utilization of muscle glycogen not essential to life

Can’t provide fuel for glycolysis to keep up

Demand for ATP

NMR on forearm muscle

Muscle cramps correlate with inc ADP

Vasodialation-muscle now has access to Glc

and fatty acids in blood