Carbohydrates as Energy Sources

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Carbohydrates as Energy Sources
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Na/K pump is key to SGLT1 function exchanges
Na for /K to maintain the gradient uses energy
(i.e., ATPase) this allows Na to drag the
monosaccharide (glucose) along through the
transport channel and into the enterocyte.
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Summary

• Complex carbs have been digested to simple sugars
• Enterocyte has absorbed them and delivered them
  to the blood

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Key Pathways in Carbohydrate Utilization

• Insulin-stimulated uptake
• Low circulating concentrations of insulin GLUT4
  is sequestered within cytosolic vesicles in
  myocytes and adipocytes
• Accumulation of glucose in blood triggers insulin
  release from pancreatic ß-cells
  Insulin-receptor signaling induces the
  redistribution of GLUT4 from intracellular
  storage sites to the plasma membrane once
  incorporated into the cell membrane, GLUT4
  facilitates the passive diffusion of circulating
  glucose down its concentration gradient
• The pathway in which GLUT4 is integrated into the
  plasma membrane begins with insulin binding to
  its receptor dimer
• The receptor dimer autophosphorylates (intrinsic
  tyrosine kinase activity) and subsequently
  activates insulin-responsive substrate-1 (IRS1),
  which initiates a series of reactions to activate
  protein kinase B (PKB)
• Once phosphorylated, PKB is in its active form
  and phosphorylates other targets that stimulate
  GLUT4 mobilization and trafficking to the plasma
  membrane
• Once inside cells, glucose is rapidly
  phosphorylated by hexokinase to form G6P it is
  this form of glucose that serves as the initial
  substrate for glycolysis
• G6P cannot diffuse back out of cells thus G6P
  serves to maintain the concentration gradient for
  glucose to passively enter cells.

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Basal State
Insulin-Stimulated
From Oatey et al. Biochem. J. (1997) 327, 637642
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Converting Sugars to an Energy Currency

• Key concepts
• Glycolysis
• TCA cycle
• Electron transport chain
• Oxidative phosphorylation

ATP
Sugar
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Glycolysis

• G6P is trapped in cell cytosol glycolysis
• occurs in cytosol

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• ATP is consumed at RXN
• 1 and 3
• 6C molecule split into two
• 3C molecules
• 3C molecule drives
• production of NADH
• and ATP
• No net ATP until PEP is
• converted to pyruvate
• Under aerobic conditions,
• NADH will be further
• utilized in mitochondria to
• power the electron trans-
• port chain (generate ATP)

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Glycolysis Summary

• C6H12O6 2 NAD 2 ADP 2 P -----gt 2 pyruvic
  acid, CH3(CO)COOH 2 ATP 2 NADH 2 H

Steps 1 and 3 - 2ATPSteps 6 and 9 4
ATPNet "visible" ATP produced 2
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With insufficient oxygen, or in cells lacking
mitochondria (RBC), pyruvate will be reduced at
the expense of NADH, to lactate by lactate
dehydrogenase.
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TCA (Citric Acid) Cycle

• Now, we are shifting from the cytosol, to the
  mitochondria
• Using C-containing molecules that originated with
  dietary carbohydrate and metabolized to
  tri-carboxylic acids , we are generating ATP and
  reducing power that will flow into the electron
  transport chain
• anything containing C and H that can be reduced
  to CO2 and H2O contains energy..oxygen serves
  as the terminal e- acceptor in the electron
  transport chain

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Key Features, TCA Cycle

• The citric acid cycle begins with Acetyl-CoA
  (ACoA) transferring its two-carbon acetyl group
  to the four-carbon acceptor compound
  (oxaloacetate) to form a six-carbon compound
  (citrate)
• The citrate then goes through a series of
  chemical transformations, losing first one, then
  a second carboxyl group as CO2. The carbons lost
  as CO2 originate from what was oxaloacetate, not
  directly from acetyl-CoA. The carbons donated by
  acetyl-CoA become part of the oxaloacetate carbon
  backbone after the first turn of the citric acid
  cycle. Loss of the ACoA-donated carbons as CO2
  requires several turns of the citric acid cycle.
  However, because of the role of the citric acid
  cycle in anabolism, they may not be lost since
  many TCA cycle intermediates are also used as
  precursors for the biosynthesis of other
  molecules.
• Most of the energy made available by the
  oxidative steps of the cycle is transferred as
  energy-rich electrons to NAD, forming NADH. For
  each acetyl group that enters the citric acid
  cycle, three molecules of NADH are produced

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Key Features, TCA Cycle

• Electrons are also transferred to the electron
  acceptor Q, forming QH2.
• At the end of each cycle, the four-carbon
  oxaloacetate has been regenerated, and the cycle
  continues
• Mitochondria in animals including humans possess
  two succinyl-CoA synthetases, one that produces
  GTP from GDP, and another that produces ATP from
  ADP
• Products of the first turn of the cycle are one
  GTP (or ATP), three NADH, one QH2, two CO2
• Because two ACoA molecules are produced from each
  glucose molecule, two cycles are required per
  glucose molecule. Therefore, at the end of both
  cycles, the products are two GTP (or ATP), six
  NADH, two QH2, and four CO2

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The Respiratory Chain

• We have generated reducing power per turn
• (1) FADH2
• (3) NADH
• (1) QH2
• But the energy currency we are after is
  ATP
• The respiratory (e-) transport chain allows us to
  finish extracting energy from what was our
  dietary carbs by oxidation of the reducing power,
  coupled to phosphorylation of ADP
• Oxidative Phosphorylation

ATP
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What are the e- transporters?
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ATP Yield

• Oxidation of NADH to NAD pumps 3 protons which
  charges the electrochemical gradient with enough
  potential to generate 3 ATP
• Oxidation of FADH2 to FAD pumps 2 protons which
  charges the electrochemical gradient with enough
  potential to generate 2 ATP.

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Respiratory Chain

• Protons are translocated across the membrane,
  from the matrix to the intermembrane space
• Electrons are transported along the membrane,
  through a series of protein carriers
• Oxygen is the terminal electron acceptor,
  combining with e- and H ions to produce water
• As NADH and FADH2deliver more H and electrons
  into the ETC, the proton gradient increases, with
  H building up outside the inner mitochondrial
  membrane, and OH- inside the membrane
• It is the energy derived from this proton
  (electrochemical) gradient that is used to drive
  phosphorylation of ADP (synthesis of ATP)

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NADH and FADH2 carry protons (H) and e- to the
electron transport chain located in the membrane.
The energy from the transfer of electrons along
the chain transports protons across the membrane
and creates an electrochemical gradient. As the
accumulating protons follow the electrochemical
gradient back across the membrane through an ATP
synthase complex, the energy of the gradient is
transferred by the ATP synthase system from the
gradient to ADP in the synthesis of ATP. At the
end of the electron transport chain, two protons,
two electrons, and half of an oxygen molecule
combine to form water. Since oxygen is the final
electron acceptor, the process is called aerobic
respiration.
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From Cell Nutrition, 3rd ed.
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Excess Energy from CH2O can be stored as fat

• De novo lipogenesis
• Acetyl CoA is the key

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Lipogenesis Key Points

• Occurs in the cytosol encompasses
• fatty acid synthesis and triacylglycerol
• synthesis
• Catalyzed by acetyl CoA carboxylase
• Requires biotin for carboxylation rxn
• Product is malonyl CoA

This is the rate limiting step.
Full activation requires excess energy as is
reflected in (1) adequate cellular ATP and low
AMP, (2) an accumulation of citrate in the TCA
cycle that ultimately exits the mitochondria via
an elaborate shuttle to return to the cytosol
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Lipogenesis Key Points

• Sequential additions of 2C units (acetyl CoA)
  results in the formation of palmitate
• (C160)
• 8 acetyl CoA 7 ATP 14 NADPH 6 H ---gt
• palmitate 14 NADP 8 CoA 7 ADP 7 Pi 6
  H2O
• Catalyzed by Fatty Acid Synthase
• an enzyme complex with 7 catalytic activities

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Lipogenesis Key Points

• Palmitate is esterified on a glycerol backbone to
  form triacyl glycerol

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Lipogenesis Key Points

• Avians and humans Liver (hepatocyte) is primary
  site of de novo lipogenesis
• Pig about 100 in the adipocyte itself
• Beef adipocyte
• Rodents adipocyte and hepatocyte, about 5050
• Dog/Cat Mixed, but probably favors hepatocyte

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Overall Summary

• Digested, absorbed and metabolized CH2O to
  convert the energy contained in the hydrocarbons
  to a usable currency, ATP
• Captured excess energy from these CH2O molecules
  in an energy dense form, suitable for storage
  (triacylglycerol), which can be mobilized to meet
  deficits that might arise later