Lecture 3: Carbohydrate Metabolism Flashcards by Tom Porter

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)

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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

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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)

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Phase 2 Enzymes: Aldolase, triose phosphate isomerase

Aldolase –> 6C into 2x 3C (DHAP/G3P)

Triose Phosphate Isomerase –> make 2 G3P
- DHAP into G3P

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Phase 3 Enzyme: Pyruvate Kinase

Pyruvate Kinase - gen. 2 pyruvate molecules from PEP
(+) - insulin, F1,6BP
(-) - alanine, ATP, glucagon (PEP enter gluconeogenesis)

IRREVERSIBLE

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What is Tarui Disease (biochemical)?

deficiency in PFK-1 (GSD VII)

- exercise-induced muscle cramps and weakness

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Where does Glucose-6-Phosphate get utilized other than Glycolysis?

Pentose Phosphate Pathway

used to make Ribose and NADPH

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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

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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

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Fasting blood glucose lvls (prediabetic and diabetic)

prediabetic - 100-125 mg/dL

diabetic > 125 mg/dL

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Hemolytic Anemia and its clinical markers

caused by premature destruction of RBCs

clinical markers: elevated lactate dehydrogenase (LDH), unconjugated bilirubin

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Fanconi-Bickel Syndrome

autosomal recessive
mutation in GLUT 2 transporter
unable to take up glucose, fructose, galactose

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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

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Precursors of Gluconeogenesis and where they enter at (G6P, G3P, DHAP, Oxaloacetate)

G6P –> galactose, glycogen
G3P –> fructose
DHAP –> glycerol, frucose
OAA –> propionate, glucogenic AA

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Fructose 1,6 Biphosphatase Deficiency

similar to Tarui disease in Glycolysis
rate limiting step disorder
present in infancy/early childhood

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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)

1. hexokinase/glucokinase 2. phosphoglucomutase (PGM) - G6P --> G1P 3. 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