Macro

Dangers of Sugar Consumption
-above 25%=decrease in Calcium, magnesium, zinc and iron
-added fructose increases BP and insulin resistance
Monosaccharides
-3-9 carbon atoms
-hydroxyl groups (bind other groups)
-carbonyl group (aldehyde or ketone); carbonyl carbon most active
-contain chiral centers
Chiral Carbon
-farther from carbonyl/anomeric carbon
-four different atoms attached
-determines L (opposite) vs. D (same)
alpha vs. beta
alpha: OH below plane of ring
beta: OH above plane of ring
Glucose
-found naturally in few foods
-product of starch digestion (starch->amylopectin->glucose)
Lactose
glucose + galactose
Sucrose
glucose + fructose
Fructose
found in fruit and honey
Galactose
not found in foods, by product of digestion
Oligosaccharides
-2-10 monosaccharides
-disaccharide most abundant
-contain glycosidic bonds (alpha=digestible, beta=non-digestible)
Maltose
malt product
isomaltose
product of digestion
lactose
milk products; oligo
Sucrose
table sugar
Lactulose
-beta 1,2 linkage; non-digestible
-lowers pH in gut by production of SCFA; kills pathogenic bacteria
-low pH keeps ammonia in gut instead of blood stream; important in advanced liver disease
-bulks stool
Short Chain Fatty Acids
butyrate, acetate and proprionate
Sucrose Polyester
-Olestra
-sucrose with 6-8 SCFA
-not recognized by lipase or amylase
-can cause anal leakage
Sucralose
-Splenda
-3 OH replaced with Cl
-becomes 600x sweeter
HFCS
-55-65% fructose to glucose
-metabolized in liver and enters below first key step in glycolysis (glucose->glucose-6-fructose)
-causes build up of glyceraldehyde-3-P which contributes to TG and FA
-lowers HDL and disrupts uric acid synthesis which increases BP
Dextrose
-glucose hydrolyzed from corn starch
-used in IV
Polysaccharides
-over 10 mono
-can be digestible or not
-has reducing (can donate e-) or non-reducing ends (can’t donate e-)
Starch
-70% amylopectin (branched) and 30% amalose
-used to thicken liquids
Glycogen
-alpha 1,4 and 1,6 linkages
-digestible
Cellulose
-non-digestible
-beta 1,4
-bulks up stool and exercises colonic muscles
Arabinose
-beta 1,4
-xylose
Pectin
-alpha 1,2 and 1,4; somewhat fermentable
-releases SCFA which decreases pH; energy source for colonisides and maintain healthy colon wall
-SCFA also shut down enzymes in cholesterol synthesis
Mouth Digestion
-salivary amylase: alpha 1,4, operates in pH=7
-inactivated in stomach (too acidic)
-continues in neonates b/c pancreatic amylase doesn’t develop until 6 mths.
Upper GI Digestion
-chyme enters deodenum->secretin and CCK release
-Secretin causes pancreas to release bi-carbonate and CCK, amylase
alpha-amylase
-digests 90% oligo into dextrins, maltriose and maltose
-binds to 5 glucose molecules and breaks between 2nd and 3rd molecule
-alpha 1,4 specific
-cannot digest alpha 1,6
Sucrase
Principle Substrate: sucrose, malto-oligo (alpha 1,4 only)
Km=18 (S) and 3 (M)
Alpha-Dextrinase
Principle Substrate: alpha dextrins (alpha 1,4 and 1,6)
Km=2-4
Glucoamylase
Principe Substrates: malto-oligosaccharides, alpha dextrins (alpha 1,4 only)
Km=1-4(M) and 1 (D)
Trehalase
Principle Substrate: Trehalose
Km=3
Beta-Galactosidase Lactase
Principle Substrate: Lactose
Km=2
SGLT1
-transfers glucose (or galactose) and Na (cotransport)
-on apical membrane
-Na is removed from enterocyte via Na/K Pump (2 come out, 3 K come in)
-against concentration gradient
GLUT2
-found in liver, pancreatic beta cells, basal lateral surface of SI, kidney
-promotes absorption from enterocyte into portal circulation
-low affinity for mono, so need very high concentration for activation
-when levels are low, liver doesn’t need, so goes to brain and RBC instead
-uses facilitated diffusion and doesn’t discriminate between mono
GLUT5
-found in SI, testes and kidney
-transports fructose from lumen into enterocyte
-uses passive diffusion (no energy use); moves downstream
GLUT1
-found on RBC, brain and low levels on all cells
GLUT3
-found on brain and low levels on all cells
GLUT4
-found on heart, muscle, adipose tissue and brain
-dependent on insulin
-transported via vesicles stimulated by insulin
-translocation of genes into vesicles which are released in the presence of insulin
Glucose and Muscles
-taken in via GLUT4 which is activated by insulin
-hexokinase catalyzes transformation from glucose to glucose-6-phosphate
-glucose trapped in muscle because glucose-6-phosphate can’t be dephos
Glucose and Liver
-enters via GLUT2 which requires very high concentrations to be active
-Glucokinase catalyzes transformation of glucose to glucose-6-phosphate; positively effected by insulin
-glucose can move back out via glucose-6-phosphotase
Control of Glucose Flux
1. Availability of substrate
2. Activity of key enzymes
Mechanisms of Enzyme Control
1. Allosteric Modification
2. Covalent Modification
3. Gene Expression
Allosteric Regulation
-pathway intermediates that either aid or inhibit enzyme activity
-positive (T->R) or negative (R->T) effectors
-catalyze non-reversible rxns
-moderated by ATP and NAD)
Covalent Modification
-reversible phosphorylation
-phosphate binding increases or decreases activity
-occurs b/c of hormonal changes
-mediated by kinase and phosphatases
-reversible
Genetic Regulation
-slow acting through transcription or translation
-induction: increase mRNA transcription or translation at ribosome
Key Control Point for Blood Sugar
LIVER
High Plasma Glucose
-High insulin
-Low glucagon
-Liver: decreases glycogenolysis
decreases gluconeogenesis
decreases glycogen synthesis
-decreases glucose output by liver and decreases plasma glucose
Glycogenolysis
conversion of glycogen polymers to glucose monomers
Gluconeogenesis
produces glucose from non carbohydrate sources such as lactate and AA
Glycogen
storage form of glucose in liver and muscles
Low Plasma Glucose
-low insulin levels
-high glucagon levels
-Liver: increase glycogenolysis, gluconeogenesis; decreases glycogen synthesis
-Leads to increase in hepatic glucose output and increased plasma glucose
Glucagon
hormone secreted from pancreas that raises blood glucose levels; opposite function of insulin
Glucose Metabolism in Liver
-stores excess glucose as glycogen
-converts glucose to pyruvate
-releases glucose to other tissues via gluconeogenesis and glycogenolysis
RBC and Glucose Metabolism
-no mitochondria
-rely on glycolytic pathway for energy
-requires oxygen
Brain and Glucose Metabolism
-can completely oxidize glucose under aerobic conditions
Muscle and Glucose Metabolism
-oxidize glucose and store for its own use
Adipose and Glucose Metabolism
can completely oxidize glucose at low levels; uses glucose
Glycolysis
-10 sequential steps that yields 38 possible ATP
-Pyruvate: 24 ATP
-2 ATP
-NADH: 6 ATP
-Glucose (if oxidized): 6 ATP
-generates glucose-6-phosphate for glycolysis, glycogen synthesis and pentose phosphate pathway
Steps in Glycolysis
Glucose->glucose-6-phosphate->fructose-6-phosphate->fructose-1-6-phosphate->glyceraldehyde-3-phosphate->1,3-bisphosphoglycerate->3-phosphoglycerate->2-phosphoglycerate->phosphoenolpyruvate->pyruvate->lactate and ATP
Glucokinase
-catalyzes transformation of glucose to glucose-6-phosphate
-high Km for glucose (needs lots of substrate)
-inactive when bound to regulatory protein (GKRP)
-high fructose-1-phosphate and low fructose-6-phosphate causes GKRP to dissociate and GK to become active
-fructose-1-phosphate only exists when fructose is high
-induced by insulin
Glucose-6-Phosphatase
-high Km for glucose-6-phosphate (need lots of substrate)
-clips phosphate so glucogen can be used as glucose
-repressed by insulin and induced by cortisol (genetic)
6-Phosphofructo-1-Kinase
-requires ATP and magnesium
-catalyzes transformation of fructose-6-phosphate to fructose-1-6-diphosphate (F16P2)
-first committed step of glycolysis
-induced by insulin and repressed by glucagon
-Positive Effectors: AMP/ADP, Fructose 2,6 diphosphate
-Negative Effectors: ATP, citrate
Fructose 1,6 Diphosphatase
-catalyzes conversion of fructose-1-6-diphosphate to fructose-6-phosphate
-induced by glucagon and repressed by insulin
-Negative Effector: AMP/ADP, fructose 2,6 diphosphate
Fructose-2,6-diphosphate
-synthesis and degredation determined by 6PF-2K or F2,6Pase respectfully
-modified covalently
Activation of F2,6Pase
-occurs during fasting
-glucagon binds to receptor and causes dissociation of G alpha complex from G protein via GDP->GTP
-G alpha complex binds to adenylate cyclase which increases cAMP
-cAMP activates protein kinase A by binding to regulatory units
-Protein Kinase A phosphorylates bifunctional enzyme which inhibits 6PF-2K and activates F2,6Pase
-favors gluconeogenesis over glycolysis
Activation of 6PF-2K
-occurs during fed state
-Insulin binds to receptors and activates secondary messengers that phosphorylate many proteins including phosphodiesterase (decreases cAMP) and protein phosphatase
-binding of insulin causes change in beta transmembrane protein
-activates tyrosine residues which autophosphorylate and serve as docking points for relay proteins that phosphorylate phosphodiesterase and protein phosphatase
-protein phosphatase dephosphorylates bifunctional enzyme and activates 6PF-2K and inhibits F2-6Pase
-favors glycolysis over gluconeogenesis
Pyruvate Kinase
-need ADP
-catalyzes transformation of phosphoenolpyruvate to pyruvate
-only found in mitochondria
-Positive effectors: F-1-6P2
-Negative effectors: ATP, acetyl coA, alanine
-Induced by insulin
Pyruvate Carboxylase and Phosphoenolpyruvate carboxykinase
-catalyze rxn of pyruvate to phosphoenolpyruvate and OAA
-needs ATP, CO2, biotin and GTP
-products are needed in more than one pathway
-Positive Effector: Acetyl CoA (PC)
-PEPCK induced by glucagon and repressed by insulin (use similar mechanism as 6FP-2K/F2-6Pase (PEPCK uses G protein and PK uses second messenger)
Pyruvate Conversion
-changed to OAA in mitochondria using PC
-OAA converted to aspartate, malate and PEP
-crosses into cytosol through the use of ADH, MDH and PEPCK
-ADH and MDH release NADH to keep gluconeogenesis going
Structural and Metabolic Differences between HFCS and sucrose
-HFCS contains glucose and fructose monomers vs. sucrose is a dissacharide
-HFCS monomers don’t need to be broken down vs. sucrose that must be cleaved
Metabolic Effects Associated with High HFCS Intake
1. Dyslipidemia
2. Hyperuricemia
3. Insulin Resistance
4. Appetite changes associated with weight gain
Uric Acid Formation from Fructose
-when fructose is changed to F-1-P it releases ADP, AMP and uric acid
Uric Acid Synthesis
AMP->IMP->Inosine->hypoxanthine->xanthine->urate
Glycogenin
-acts as primer for growing chain on glycogen
-has glucosyl transferase: catalyzes bond between glucose and glycogen
-glucose linked via alpha 1,4 and 1,6 bonds at branched points
Glycogen Synthesis in Liver
Glucose->G-6-P->G-1-P->glycogen primer->elongation using 2 UDP=glycogen
Elongation of Glycogen
-UDP-glucose gives up glucose to non-reducing end
-forms alpha 1,4 glycosidic bond
-branching enzyme takes over and cleaves a bond 4-6 units from branch point
-forms alpha 1,6 bond which provides new site for elongation
Carb Content of Foods
Milk: 12
Bread/Cereal: 15
Vegetables: 5
Fruit: 15
Deserts: 15
Guidelines for Sugar Consumption
Dietary Guidelines for Americans: 6%
Institute of Medicine: no more than 25%
World Health Organization: no more than 10%
Average teen: 16%
Cyclic Sugars
Formed by rxn of hydroxyl group of C-5 with anomeric carbon on C-1
Salivary Amylase
specific for alpha 1,4 bonds
Amylase Digestion Products
dextrins, maltriose and maltose
Hypolactasia
as we get older we consume less lactose and lactase decreases as a result
Range of Normal Blood Sugar
80-126 mg/dl
Fate of G-3-P
Eventually turns into triglyceride backbone via glycerol-3-phosphatase
Uses of Glucose-6-Phosphate
-glycolysis
-glycogen synthesis
-pentose phosphate pathway (ribose 5 phosphate synthesis)
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