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Foundations 1 > Glucose Metabolism > Flashcards

Glucose Metabolism Flashcards

1
Q

What are the different glucose transporter isoforms, what are their functions, and where are they expressed?

A
  • GLUT1 = uptake of basal glucose to sustain respiration in adult cells (especially erythrocytes and endothelial cells of barrier tissues); fetal tissues. Regulated by cellular glucose levels and upregulated in tumors. Class I.
  • GLUT2 = bidirectional, high-frequency, low-affinity transporter. Renal tubular cells, liver cells (in = glycolysis / out = gluconeogenesis), pancreatic beta cells (flow of glucose allows gauging of serum glucose), basolateral membrane of small intestinal epithelium. Class I.
  • GLUT3 = high-affinity (allowing transport even when [glu] is low). Neurons and placenta. Class I.
  • GLUT4 = Adipose tissues and striated muscle; insulin regulated. Class I.
  • GLUT14 = Testicular optic canals and similar to GLUT3. Class I.
  • GLUT5,7,9,11 = Class II. GLUT5 = fructose transport in enterocytes. GLUT7 = intestinal epithelium.
  • GLUT6,8,10,12,13 = Class III.
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2
Q

Describe the function of hexokinase and the different hexokinase isoforms.

A
  • Phosphorylates glucose to form G6P, trapping it in the cell (charged molecule cannot recross membrane)
  • HKI = Mitochondrial surface, involved in glycolysis, regulated by G6P (inh) and Pi (act)
  • HKII = Mitochondrial surface, involved in glycogen synthesis and PPP, regulated by G6P (inh) and Pi (inh)
  • HKIII = Perinuclear, glycogen synthesis and PPP, regulated by G6P (inh) and Pi (inh)
  • HKIV (glucokinase) = Cytoplasmic and nuclear, glycolysis, not inhibited
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3
Q

What are the possible fates of G6P?

A

glycolysis, PPP, glycogen synthesis, glycoproteins/glycolipids, proteoglycans, glucuronides

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4
Q

What is the purpose of glycolysis and where does it occur?

A
  • Generates energy aerobically or anaerobically from glucose: 1 mol glucose -> 2 mol pyruvates = 2 ATP + 4 electrons
  • Cytosol
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5
Q

What are the two phases of glycolysis?

A
  1. Preparative phase: generates high energy molecule (fructose-1,6-BP) from glucose
  2. Energy rearrangement phase
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6
Q

What are the steps of glycolysis?

A
  1. Glucose => G6P: phosphorylation by HK, uses 1 ATP
  2. G6P => F6P: rearrangement by isomerase
  3. F6P => F-1,6-BP: phosphorylation by PFK-1, uses 1 ATP
  4. F-1,6-BP => DHAP + GAP (both 3C molecules)
  5. DHAP <=> GAP: rearrangement isomerase, equilibrium favors GAP because GAP rapidly removed by GAPDH
  6. GAP => 1,3-BPG: oxidation by GAPDH, generates 1 NADH
  7. 1,3-BPG => 3-PG: dephosphorylation by kinase, generates 1 ATP via substrate level phosphorylation
  8. 3-PG => 2-PG: rearrangement by mutase
  9. 2-PG => PEP: rearrangement by enolase
  10. PEP => pyruvate: dephosphorylation by pyruvate kinase, generates 1 ATP
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7
Q

How is energy generated from NADH in aerobic glycolysis?

A
  • Transferred by G3P and malate-aspartate shuttles into mitochondria
  • oxidative phosphorylation in ETC regenerates NAD+
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8
Q

How is energy generated from NADH in anaerobic glycolysis?

A
  • Pyruvate is reduced to lactate by LDH, requiring the oxidation of 1 NADH
  • Lactate re-oxidized to pyruvate in the liver
  • Occurs in cells without mitochondria (kidney medulla, RBCs)
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9
Q

What are the regulatory points in glycolysis?

A
  • HK inhibited by G6P
  • PFK-1 is allosterically regulated. Activated by AMP and F-2,6-BP (which is regulated by insulin/glucagon ratio). Inhibited by ATP and citrate
  • Liver PEP isozyme is activated by F-1,6-BP (feed forward) and inhibited by ATP
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10
Q

How can fructose enter glycolysis?

A
  1. Conversion to sorbitol and then glucose
  2. Conversion to G3P
    - Fructose => F6P: phosphorylation by fructokinase, requires 1 ATP
    - F6P => DHAP + glyceraldehyde: cleavage by aldolase B (liver) or aldolase A (muscle)
    - Glyceraldehyde => GAP: phosphorylation triose kinase, requires 1 ATP
    - GAP and DHAP can enter glycolysis
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11
Q

What diseases are associated with fructose metabolism?

A
  • Too much dietary fructose => sorbitol buildup => osmotic issues
  • Essential fructosuria: Autosomal recessive, mutation to fructokinase. Fructose builds up and is excreted in urine
  • Inherited fructose intolerance: aldolase B mutation. Can cause depletion of liver ATP
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12
Q

How can galactose enter glycolysis?

A
  1. Galactose => Gal1P: phosphorylation by galactokinase (GALK), requires 1 ATP
  2. Gal1P => Glu1P: galactose-1-P-uridylyltransferase (GALT), exchange reaction with UDP-glucose => UDP-galactose.
  3. UDP-gal => UDP-glu: epimerization via GALE
  4. Glu1P => Glu6P via polyol pathway
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13
Q

Which enzymes are inhibited in galactosemias?

A
  • Non-classical galactosemia = GALK (step 1)
  • Classical galactosemia = GALT (step 2)
  • Neither clinically severe
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14
Q

What is the consequence of erythrocytic pyruvate kinase deficiency?

A

Hemolytic anemia: insufficient ATP production to suppose Na-K ATPase activity in plasma membrane

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15
Q

What are the symptoms of F-1,6-bisphosphatase deficiency?

A

Compromised gluconeogenesis, fasting hypoglycemia, ketosis, acidosis

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16
Q

What is the Warburg Effect?

A
  • Tumor cells need lots of ATP and R5P => increased rate of glycolysis and PPP
  • High glycolysis rate works well in anaerobic environment
17
Q

What biosynthetic pathways might glycolytic intermediates enter?

A
  • G6P: 5 carbon sugars, triglycerides
  • 1,3-BPG: 2,3-BPG
  • 3-PG: serine, 2,3-BPG
  • Pyruvate: alanine, acetyl coA -> TCA cycle -> amino acids, acetyl coA -> FAs
18
Q

Describe the steps of the polyol pathway.

A
  1. Glucose => sorbitol. Reduction by aldose reductase, requires 1 NADPH
  2. Sorbitol => fructose. Oxidation by sorbitol dehydrogenase, requires 1 NAD+
  • Same steps with galactose (intermediate = galactitol)
19
Q

What is glycation?

A
  • Nonenzymatic addition of reducing sugars to proteins
  • Sugars can spontaneously covalently bond with certain amino acids
  • Leads to production of advanced glycation end products (AGEs)
  • Very slow process
  • AGEs involved in cross-linking with ECM, oxidative stress, neovascularization, inflammation
20
Q

When and where does the PPP occur?

A
  • Cytoplasm

- Well fed, low energy consumption, growth, need for reducing agents

21
Q

What are the main products of the PPP?

A
  • 2 NADPH => FA synthesis, glutathione (antioxidant) reduction, drug detox
  • R5P => nucleotide biosynthesis
22
Q

Describe the oxidative phase of the PPP.

A
  1. G6P => 6-phosphogluconolactone: Oxidation by G6PD, generates 1 NADPH, requires Ca or Mg ions
  2. 6-phosphogluconolactone => 6-phosphogluconate: hydration by gluconolactone hydrolase, requires water and Mg, Mn, or Ca ions
  3. 6-phosphogluconate => Ribulose-5-phosphate: oxidative decarboxylation by 6-phosphogluconate dehydrogenase, generates 1 NADPH and CO2, requires Mg, Mn, or Ca ions

Net: G6P + 2 NADP+ + water -> R5P + 2NADPH + 2H+ + CO2

23
Q

What diseases are associated with the PPP?

A

G6PD is the most common inherited enzyme deficiency

24
Q

When and where does gluconeogenesis occur? What are the energy requirements?

A
  • Mitochondria and cytoplasm of liver, kidney, intestine
  • Fasting, starvation, low-carb diet, intense exercise
  • 4 ATP + 2 GTP per glucose
25
Q

At what points does gluconeogenesis differ from glycolysis in reverse?

A
  • G6P => glucose: HK replaced by glucose-6-phosphatase
  • F-1,6-BP => F6P: PFK-1 replaced by fructose bisphosphatase
  • Pyruvate => PEP: pyruvate carboxylated to OAA by pyruvate carboxylase then OAA decarboxylated and phosphorylated to PEP by PEP carboxykinase requiring 1 GTP
26
Q

What are the glucogenic amino acids and what gluconeogenic intermediates do they form?

A
  • pyruvate: thr, gly, trp, ala, ser, cys
  • OAA: asp, asn
  • fumarate: asp, tyr, phe
  • propionyl CoA (succinyl CoA precursor): val, thr, ile, met
  • a-ketoglutarate: arg, his, gln, pro, glu
27
Q

How is pyruvate converted to PEP?

A
  1. Pyruvate => OAA: carboxylation by pyruvate carboxylase in the mitochondrion, requiring 1 Acetyl CoA + 1 ATP + biotin cofactor
  2. OAA converted to malate (via malate DH, requiring 1 NADH) or aspartate (via transamination) and transported to cytosol via malate/aspartate shuttles.
  3. Conversion back to OAA via reverse mechanism (if malate, will generate 1 NADH)
  4. Phosphorylation and decarboxylation by PEPCK, requiring 1 GTP
28
Q

What additional enzymes are regulated during gluconeogenesis?

A
  • Pyruvate kinase is inhibited under gluconeogenesis conditions (glucagon -> phosphorylation of PK -> inactivation)
  • PDH inhibited by NADH coming from B-oxidation
  • Pyruvate carboxylase activated by acetyl CoA from B-oxidation
  • PEPCK is induced transcriptionally
  • Fructose-1,6,-bisphosphatase is activated and induced
  • glucose-6-phosphatase induced
29
Q

How are opposing enzymes in gluconeogenesis/glycolysis regulated?

A
  • Glucokinase vs glucose-6-phosphatase: GK has a high Km
  • PFK-1 vs Fructose-1,6-bisphosphatase: PFK-1 is inhibited by ATP and alloseterically activated by AMP and F-2,6-P. Fructose-1,6-bisphosphatase is allosterically inhibited by AMP (and in the liver, by F-2,6-BP) and allosterically activated by ATP.
  • Pyruvate kinase vs pyruvate carboxylase/PEPCK: PK deactivated by phosphorylation from cAMP signaling
30
Q

Describe the structure of glycogen.

A
  • Branching glucose polymer with linear a-1,4 and branching a-1,6 linkages. More branching allows for more storage and degradation in parallel.
  • Non-reducing (-OH) ends exposed and attached to glycogenin and reducing ends
31
Q

Describe the process of glycogen synthesis.

A

Same process at all non-reducing ends:

  1. G6P => G1P: phosphoglucomutase rearranges
  2. G1P => UDP-Glu: addition of UDP
  3. Glycogen synthase transfers glucose from UDP to glycogen chain with a-1,4 link
  4. every 6 additions, 4:6 transferase (branching enzyme) moves a chain of 6 glucoses to the main chain and links via a-1,6 linkage
32
Q

Describe the process of glycogen degradation.

A
  1. Glycogen phosphorylase uses Pi to remove G1P’s
  2. When branch length = 4, 4:4 transferase moves 3 from the branch to the main chain.
  3. a-1,6 linked glucose is removed by a-1,6-glucosidase

Foundations 1 (26 decks)

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