Lecture 3: Carbohydrate Metabolism Flashcards
What are GLUTs?
Glucose transporters that bring glucose into cells
GLUT 1 –> RBCs/Brain
GLUT 2 –> Liver (LOW AFFINITY)
GLUT 3 –> Neurons
GLUT 4 –> Cardiac, Skeletal, Adipose cells
- INSULIN DEPENDENT (Upregulates expression)
What are the 3 phases of Glycolysis?
Phase 1: Investment –> use 2 ATP
Phase 2: Splitting –> one 6C into two 3C
Phase 3: Payoff –> generate 4 ATP
Phase 1 Enzymes: Hexokinase, Glucokinase, Phosphofructokinase-1
Hexokinase (all cells)
(-) - G6P
Glucokinase (liver, pancreatic B cells)
(+) - glucose, F1P, insulin
(-) - glucagon, F6P
Phosphofructokinase-1 RATE LIMITING STEP (Glycolysis)
(+) - AMP, F2,6BP
(-) - ATP, Citrate
F2,6BP formed via PFK-2/FBPase-2 (bifunctional)
Phase 2 Enzymes: Aldolase, triose phosphate isomerase
Aldolase –> 6C into 2x 3C (DHAP/G3P)
Triose Phosphate Isomerase –> make 2 G3P
- DHAP into G3P
Phase 3 Enzyme: Pyruvate Kinase
Pyruvate Kinase - gen. 2 pyruvate molecules from PEP
(+) - insulin, F1,6BP
(-) - alanine, ATP, glucagon (PEP enter gluconeogenesis)
IRREVERSIBLE
What is Tarui Disease (biochemical)?
- deficiency in PFK-1 (GSD VII)
- exercise-induced muscle cramps and weakness
Where does Glucose-6-Phosphate get utilized other than Glycolysis?
Pentose Phosphate Pathway
- used to make Ribose and NADPH
Effects of Glycolysis deficiency on Red Blood Cells
- lack mitochondria, glycolysis only means to gen. ATP
- no glycolysis –> ATP deficiency (ion gradient ruined)
- dec. cell viability, RBC destruction = hemolytic anemia
What is Diabetes and what are some of the problems caused by it?
- disease characterized by hyperglycemia
Type 1: insulin deficiency (Pancreatic B cells lost)
Type 2: insulin resistance (loss of B cells functions)
causes: mutations (GK, mito tRNA genes), aberrant proinsulin –> mature insulin conversion, defective receptors
symptoms: elevated BGL, polydipsia, polyuria, unexplained weight loss
Fasting blood glucose lvls (prediabetic and diabetic)
prediabetic - 100-125 mg/dL
diabetic > 125 mg/dL
Hemolytic Anemia and its clinical markers
- caused by premature destruction of RBCs
clinical markers: elevated lactate dehydrogenase (LDH), unconjugated bilirubin
Fanconi-Bickel Syndrome
- autosomal recessive
- mutation in GLUT 2 transporter
- unable to take up glucose, fructose, galactose
What are the 4 regulatory enzymes of Gluconeogenesis?
- Pyruvate Carboxylase (BIOTIN cofactor)
(+) - acetyl CoA, cortisol
(-) - ADP - PEP Carboxykinase (PEP CK)
(+) - cortisol, glucagon, thyroxine - Fructose 1,6, Biphosphatase (RATE LIMITING STEP)
(+) - citrate, cortisol
(-) - AMP, F2,6BP - Glucose-6-Phosphatase
(+) - cortisol
Precursors of Gluconeogenesis and where they enter at (G6P, G3P, DHAP, Oxaloacetate)
- G6P –> galactose, glycogen
- G3P –> fructose
- DHAP –> glycerol, frucose
- OAA –> propionate, glucogenic AA
Fructose 1,6 Biphosphatase Deficiency
- similar to Tarui disease in Glycolysis
- rate limiting step disorder
- present in infancy/early childhood
Von Gierke disease (GSD Ia)
deficiency in glucose-6-phosphatase
- inefficient release of free glucose into bloodstream in liver
What do GLUT5, GLUT2, and SGLT1 transport?
GLUT5 –> fructose
GLUT2 –> glucose, galactose, fructose
SGLT1 –> fructose, galactose, sodium
Polyol Pathway (Sorbitol) and problem
glucose –> sorbitol (aldose reductase)
sorbitol –> fructose (sorbitol dehydrogenase)
no sorbitol dehydrogenase = sorbitol buildup
- water influx, swelling –> retinopathy, cataracts, peripheral neuropathy
What is the rate limiting step of galactose metabolism?
GALT
glucose 1P uridyltransferase
Fructose Metabolism and excessive consumption
- much faster than glucose metabolism
- bypasses rate limiting step of glycolysis (no PFK-1)
- G3P/DHAP from unregulated synthesis
- excess ACoA –> FA, transported to adipocytes –> TAGS (obesity)
- liver accumulates FA (fatty liver)
Lactose Intolerance
- cannot metabolize lactose (milk = GI disturbances)
- deficiency in lactase (break down lactase into glucose/galactose)
Galactosemia (GALT and Galactokinase)
- GALT deficiency –> galactitol accumulation
- classic galactosemia: liver failure, sepsis, bleeding
- Galactokinase deficiency
- nonclassical type: galactose/galactitol in blood/urine
- galactitol (eye) –> cataracts (early infancy)
Cataracts
- clouding of normally clear lens of eye
- transferase not active, aldolase reductase converts galactose to galactitol
Pentose Phosphate Pathway
- no NRG production, produces NADPH and sugars for RNA/DNA formation
- in cytosol; oxidation G6P to ribulose 5-P
- irreversible oxidative step and reversible non-oxidative step
Oxidative Phase PPP and G6P dehydrogenase
G6PD –> RATE LIMITING ENZYME (NADP –> NADPH)
- NADPH regenerates glutathione (antioxidant)
- G6PD deficiency –> hemolytic anemia
Nonoxidative Phase PPP and transketolase/transaldolase
- regenerative phase (reversible)
- end products go to glycolytic, gluconeogenic, nucleotide synthesis pathways
transketolase: TTP required, transfer of 2C
transaldolase: transfer of 3C
Glycogen Structure
- long homopolymer of glucose molecules
a-1,4 glycosidic bonds (long chain bonds)
a-1,6 glycosidi bonds (branch points)
reducing end: glucose monomer w/glycogenin
non reducing end: where degraded/extended from
glycogenin –> serves as primer for glycogen synthesis
Glycogen Storage and Functions
- stored in liver, muscles as granules
granules also contain enzymes needed for metabolism
liver function: BGL regulation
muscle function: reservoir of fuel for activity
Glycogenesis Enzymes (Trapping Glucose)
- hexokinase/glucokinase
- phosphoglucomutase (PGM)
- G6P –> G1P
- UDP-glucose pyrophosphophorylase
- G1p –> UDP-glucose (active form)
Glycogenesis Enzymes (elongation and branching)
Elongation: Glycogen Synthase (RATE LIMITING STEP)
- glucose (UDP-glucose) added to glycogen primer
- a-1,4 glycosidic bond
Branching: glucosyl (4:6) transferase
- chain is 11 long, 7 break off to make branch
- a-1,6 glycosidic bond
- increases solubility of glycogen
Glycogenolysis Enzymes (shortening and release)
Shortening: Glycogen Phosphorylase (RATE LIMIT STEP)
- uses B6 as cofactor
- removes glucose until gets to 4 residues
Release: debranching enzyme
- transfer 3 of 4 glucose to non-reducing end
- cleaves a-1,6 glycosidic bond to release glucose
Normal, Prediabetic, Diabetes mellitus fasting and fed glucose levels
Normal
- Fasting: 70-100 mg/dL
- Fed: =/< 140 mg/dL
Prediabetic
- Fasting: 100-125 mg/dL
- Fed: > 140 mg/dL
Diabetes Mellitus
- Fasting: =/> 126 mg/dL
- Fed: =/> 199 mg/dL
GSD 0
- deficiency in glycogen synthase
- cannot synthesize/store glycogen
- muscle cramps, need to eat frequently
GSD1a
- Von Gierke disease
- deficiency in glucose 6-phosphatase
- cannot release free glucose into blood stream (liver)
GSD II
- Pompe disease
- deficiency in Acid Maltase (acid a-glucosidase)
- impairs lysosomal glycogenolysis (glycogen accumulation in lysosomes
- progressive muscle weakness (myopathy)
GSD III
- Cori Disease
- deficiency in a-1,6 glucosidase (debranching enzyme)
- glycogen w/LARGE # short branches
- light hypoglycemia and hepatomegaly
GSD IV
Andersen Disease
- deficiency in glucosyl (4:6) transferase (branching enzyme)
- long chain glycogen w/fewer branches
- spleen/liver enlargement, tissue scarring (cirrhosis)
GSD V
McArdle Disease
- deficiency in muscle glycogen phosphorylase
- unable to supply muscles w/enough glucose
- muscle breakdown (Myoglobinuria), myoglobin in urine
GSD VI
Hers Disease
- deficiency in liver glycogen phosphorylase
- prevent glycogen breakdown in liver (hepatomegaly)
- low blood glucose lvls that cannot be brought up
