Lec Notes - Carbohydrate Metabolism (Glycolysis, Kreb Cycle, ETC)

CARBOHYDRATE METABOLISM

Overview of Metabolism

Prepared by: Dr. Marites D. Saludares / Chemistry Department, UST College of Science / mdsaludares@ust.edu.ph

Glycolysis


SUMMARY OF GLYCOLYSIS REACTIONS

Energy-‐investing reaction:
Step 1: molecule of glucose (C6) + 1st ATP glu-‐6-‐phosphate
reaction: phosphorylation enzyme: hexokinase

Step 2: glu-‐6-‐phosphate fru-‐6-‐phosphate
reaction: isomerization enzyme: phosphoglucoisomerase

Energy-‐investing reaction:
Step 3: fru-‐6-‐phosphate + 2nd ATP fru-‐1,6-‐biphosphate
reaction: phosphorylation enzyme: phosphofructokinase

C6 to two C3 fragments:
Step 4: fru-‐1,6-‐biphosphate dihydroxyacetone phosphate
gly-‐3-‐phosphate
reaction: cleavage/splitting enzyme: aldolase

Step 4A:
dihydroxyacetone phosphate gly-‐3-‐phosphate
reaction: isomarization enzyme: triosephosphate isomerase

Energy-‐harvesting reactions/ ATP productions (Steps 5 – 9, reactions will occur TWICE):
Step 5: gly-‐3-‐phosphate + NAD+ 1,3-‐diphosphoglycerate + NADH
reaction: oxidative phosphorylation enzyme: gly-‐3-‐phosphate dehydrogenase

Step 6: 1,3-‐diphosphoglycerate + ADP 3-‐phosphoglyceric acid + 1st ATP
reaction: substrate level phosphorylation enzyme: phosphoglycerate kinase
(transfer of phosphate to ADP)

2 mol of 1,3-‐diphosphoglycerate = 2 ATPs

Step 7: 3-‐phosphoglyceric acid 2-‐phosphoglyceric acid
reaction: transfer of phosphate enzyme: phosphoglycerate mutase
from C3 to C2

Step 8: 2-‐phosphoglyceric acid phosphoenolpyruvate
reaction: dehydration enzyme: enolase


Pyruvic acid synthesis
Step 9: phosphoenolpyruvate + ADP pyruvic acid + 2nd ATP
reaction: substrate level phosphorylation enzyme: pyruvate kinase

2 mol of phosphoenolpyruvate = 2 ATPs

ATP PRODUCTION OF CYTOPLASMIC NADH
§ reaction occurs twice since there are 2 mol of gly-‐3-‐phosphate
§ 1 cytoplasmic NADH yields ONLY 2 ATPs
§ since cytoplasmic NADH is impermeable to mitochondrial membrane, energy is expended to
shuttle NADH into the mitochondria
§ 2 NADH x 2 ATPs = 4 ATPs

ATP PRODUCTION OF MITOCHONDRIAL NADH (in Kreb Cycle)
§ 1 mitochondrial NADH yields 3 ATPs

ROLES OF NAD+, NADH and ADP
§ NAD+ acts as oxidizing agent
§ NAD+ signals oxidation/ dehydrogenation reaction or oxidative phosphorylation; yields NADH
§ NADH acts as reducing agent
§ NADH signals reduction/ hydrogenation reaction; yields NAD+
§ ADP signals substrate level phosphorylation; yields ATP

ATPs produced from glycolysis:
§ glycolysis occurs in the cytoplasm
§ glucose (C6) is split into two (C3) fragments
§ two C3 fragments yield 2 pyruvic acids (to enter the Kreb Cycle)
§ end products of glycolysis from 1 mole of glucose:
2 pyruvic acids + 2 NADH (4 ATPs) + 4 ATPs = 8 ATPs

NET TOTAL: 6 ATPs ONLY from glycolysis (why?)


Kreb Cycle


SUMMARY OF KREB CYCLE REACTIONS

Initial Reaction: Pyruvic acid to acetyl CoA (in the cytoplasm):
for 1 mol of glucose:
2 pyruvic acids + HS-‐CoA + NAD+ 2 acetyl-‐CoA + CO2 + 2 NADH x 3 ATPs = 6 ATPs
reactions: oxidative decarboxylation,
condensation with CoA-‐SH
enzyme: pyruvate dehydrogenase to enter mitochondria: Kreb Cycle

Kreb Cycle (in the mitochondria):
Step 1: oxaloacetic acid + acetyl-‐CoA + H2O citric acid + CoA-‐SH
reactions: removal of CoA-‐SH, enzyme: citrate synthase
condensation
* oxaloacetic acid (a keto-‐acid), acts as acetyl-‐CoA acceptor

Steps 2-‐3: citric acid isocitric acid
reactions: dehydration, hydration enzyme: cis-‐aconitate

Steps 4-‐5: isocitric acid + NAD+ α-‐ketoglutaric acid + CO2 + NADH
reaction: oxidative decarboxylation enzyme: isocitrate dehydrogenase

Step 6: α-‐ketoglutaric acid + NAD+ + CoA-‐SH succinyl-‐CoA + CO2 + NADH
reactions: oxidative decarboxylation, enzyme: α-‐ketoglutarate dehydrogenase
condensation

Step 7: succinyl-‐CoA + ADP succinic acid + CoA-‐SH + ATP
reactions: removal of CoA-‐SH, enzyme: succinyl-‐CoA synthetase
substrate level phosphorylation

Step 8: succinic acid + FAD fumaric acid + FADH (equals 2ATPs)
reaction: oxidation enzyme: succinate dehydrogenase

Step 9: fumaric acid + H2O malic acid
reaction: hydration enzyme: fumarase

Step 10: malic acid + NAD+ oxaloacetic acid + NADH
reaction: oxidation enzyme: malate dehydrogenase


ATPs produced from Glycolysis (in the cytoplasm):
§ end products of glycolysis:
1 glucose 2 pyruvic acids + (2 NADH x 2ATPs) + (4 ATPs – 2 ATPs) = 6 ATPs

Pyruvic acid to acetyl CoA (in the cytoplasm):
+
§ 2 pyruvic acids + HS-‐CoA + NAD 2 acetyl-‐CoA + CO2 + 2 NADH x 3 ATPs = 6 ATPs
enzyme: pyruvate dehydrogenase (to enter mitochondria: Kreb Cycle)

ATPs produced from Kreb Cycle (in the mitochondria):
3 NADH x 3 ATPs = 9 ATPs
1 FADH x 2 ATPs = 2 ATPs
1 ATP = 1 ATP
NET TOTAL: 12 ATPs x 2 turns of the cycle = 24 ATPs

OVERALL ATP PRODUCTION = 36 ATPs per 1 mol of glucose


Electron Transport Chain

outer membrane

intermembrane space

inner membrane

matrix

§ NADH produced from glycolysis are shuttled into the mitochondrial matrix where these NADH
are re-‐oxidized to NAD+, while forming H+ ions (protons) and electrons (e-‐)
NADH NAD+ + H+ + e-‐
§ as NADH produced from Kreb cycle delivers more H+ and e-‐, these protons (H+) and e-‐ are
translocated via specialized protein channels (co-‐enzymes) across the membrane
§ translocation is from the matrix into the intermembrane space increasing the proton gradient
in the intermembrane space
§ protons from the intermembrane space enter once again, the mitochondrial matrix through
ATP synthase
§ ATP continues to be made as protons move through ATP synthase enzyme
§ oxygen is the final electron acceptor , combining with H+ ions to produce water


§ under anaerobic conditions, the NADH is used as a reducing agent to reduce pyruvic acid to
lactic acid


HW on Carbohydrate Metabolism
GYCOLYSIS
Glycolysis pathway: after digestion of carbohydrates, glucose enters the cell membrane and into the
cytoplasm, GLYCOLYSIS takes place where glu-6-P (a 6C-molecule) is split into two 3C molecules of
gly-3-P, producing 2 pyruvic acids.
The two pyruvic acids are then converted to two acetyl-CoA and enter the mitochondria where KREB
CITRIC ACID cycle occurs.
1) What reaction is involved in the so called, energy-investing reactions? What chemical compound is
needed to initiate the reaction?
2) The conversion from glu-6-P to fru-6-P involves isomerization. What is an isomer?
3) What stages in the glycolysis pathway are considered energy harvesting reactions? What are the
products of these reactions that will prove its energy yield?
4) The conversion from gly3-P to 1,3-diP uses NAD+ and a dehydrogenase enzyme. What is the role
of NAD+? What reactions therefore are involved in these conversions?
5) The formation of pyruvic acid (a keto-acid) involves what reaction? Account for the total ATP
produced from glycolysis.
KREB CYCLE
The 2 moles of pyruvic acids produced per molecule of glucose from glycolysis in the cytoplasm,
enters the mitochondria, successively.
Initial Reaction:
pyruvic acid + Co-ASH (co-enzyme A) + NAD+ to produce acetyl CoA + CO2 + NADH + H+ ion as
products.
1) In the Initial reaction, considering the products in the conversion of pyruvic acid to acetyl-CoA,
aside from the condensation reaction of pyruvic acid with CoA-SH, what is the other reaction
involved?
2) In Step 1, how many carbon atoms are there in citric acid? What reactions between acetyl-CoA
and oxaloacetic acid are involved in forming citric acid?
3) In Steps 2 and 3, what are the reactions involved in forming isocitric acid?
4) In Steps 4 and 5, the conversion of isocitric to α-ketoglutaric acid uses NAD+ to produce NADH and
CO2, what are the reactions involved? Compare the no. of carbon atoms between isocitric and α-
ketoglutaric acid.


5) In Step 6, the conversion of α-ketoglutaric acid to succinyl CoA requires the removal of CO2 using
NAD+ and Co-ASH to produce NADH and succinyl-CoA. What reactions are involved in producing
succinyl-CoA? Compare the no. of carbon atoms between α-ketoglutaric acid and succinyl CoA.
6) In Step 7, 1 mole of ATP is produced in the conversion of succinyl CoA to succinic acid? What
reactions are involved?
7) In Step 8, the conversion of succinic to fumaric acid uses FAD (same role as NAD+). What
reaction is involved? Identify the change in the functional group.
8) In Step 9, the conversion of fumaric to malic acid, what reaction is involved?
9) In Step 10, the conversion of malic to oxaloacetic acid uses NAD+. What is the reaction involved?
Identify the change in the functional group.
10) Account for the sum total of ATP produced from glycolysis and Kreb cycle.
ELECTRON TRANSPORT CHAIN (ETC)
Cross section of the mitochondria consists of:

1) outer membrane
2) intermembrane space
3) inner membrane
4) mitochondrial matrix
The inner membrane has specialized protein channels (co-enzymes) where H+ ions and electrons
pass through and get translocated, from inner to the intermembrane space.
1) As NADH generated from Kreb cycle moves to a co-enzyme and delivers its H+ ions and electrons,
what happens to NADH?
2) As H+ ions remain in the intermembrane space, electrons are continuously passed on through
series of co-enzymes. Which acts as the final acceptor of electrons?
3) What compound is produced when electrons react with the final acceptor?
4) As H+ ion increases in the intermembrane space, the proton gradient also increases. What is the
effect of this increase in proton gradient on the H+ ions?


Lec Notes - Carbohydrate Metabolism (Glycolysis, Kreb Cycle, ETC)

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SUMMARY OF GLYCOLYSIS REACTIONS

2) The conversion from glu-6-P to fru-6-P involves isomerization. What is an isomer?

8) In Step 9, the conversion of fumaric to malic acid, what reaction is involved?

ELECTRON TRANSPORT CHAIN (ETC)

Cross section of the mitochondria consists of:

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