Transcript The Central Role of Acetyl-CoA

MOLECULES IN METABOLISM
Metabolic Chemistry Related to
Overweight
Reactions and molecules in the
digestive process
THE FATE OF FOOD
• Food is digested to produce molecules that are used to
support life
• In the context of body weight the fate of three classes of
food are central
o Carbohydrates (sugars)
o Lipids (fats)
o Amino acids (from proteins)
• The metabolisms of all three overlap
METABOLIC CHEMISTRY
• Catabolism and Anabolism
• Molecular constituents of food are broken down into
smaller molecules (catabolism)
o for reassembly into larger molecules (anabolism)
such as fats or proteins
o for oxidation to CO2 and H2O and energy
• A balance is required to maintain a stable organism homeostasis
ENERGY STORAGE
• Energy produced in metabolism is stored in an energyrich molecule ATP
• Adenosine triphosphate ATP – the battery of life
• Biological processes requiring energy use ATP
• The accessible energy in ATP lies in the triphosphate
link
• Removing one phosphate gives adenosine diphosphate
(ADP) plus energy.
ADENOSINE TRIPHOSPHATE, ATP
energy-storage bond
triphosphate
adenosine
ENERGY STORAGE IN ATP
Adenosine triphosphate (ATP)
-
H2O
-
-
-
energy released
H3PO4
H2O
energy stored
H3PO4
-
-
The human body produces and
consumes its own mass in ATP each day
Adenosine diphosphate (ADP)
ENERGY PRODUCTION IN THE CELL
• Energy is produced by oxidation of molecular fuels small molecules derived from carbohydrates, lipids,
proteins
• The oxidation uses oxidised forms of coenzymes
ultimately producing CO2, H2O and stored energy
• Energy is stored directly as ATP or as reduced forms of
coenzymes that ultimately reduce oxygen to H2O
• Reduction of oxygen to H2O yields more ATP and
oxidised form of coenzymes
MOLECULES IN METABOLISM
• Organic molecules from metabolised nutrients often
enter metabolic pathway reactions bound to a
coenzyme.
• Coenzyme A is an important coenzyme
• Phosphate is often bound to organic molecules
• Oxidation/reduction (electron transport) reactions use
NADH
NAD+
COENZYME A
Usually written as HS-CoA
HS-CoA activates organic molecules for metabolic reactions
by binding through HS-group to give reactive “–CoA” species
Acetyl-CoA is an important example
NICOTINAMIDE ADENINE DINUCLEOTIDE
(NAD)
phosphate
nicotinamide
1
phosphate
adenine
Important in oxidation/reduction reactions
NAD+ AS AN OXIDISING AGENT
• NAD+ is the main coenzyme for oxidation reactions of
metabolic fuels for energy
• NAD+ oxidises other molecules forming NADH and H+
• NADH is oxidised back to NAD+ indirectly by oxygen to
give H2O (the electron transport chain)
• For each molecule of NADH reoxidised 2.5 molecules of
ATP are produced from ADP
• So energy from oxidising metabolic fuels is stored as ATP
ACETYL CoA – THE CROSSROADS
carbohydrates
glycogen
proteins
glucose
fats
glycolysis
pyruvate
fatty acids
oxidation
amino acids
fatty acid
oxidation
acetyl-CoA
fatty acid
synthesis
citric acid
cycle
CO2 + energy
Glucose in excess of metabolic needs results in fat deposition
SOURCES OF ACETYL CoA
• Three metabolic reactions of food components
produce are linked
o Glycolysis of glucose
o Oxidation of fatty acids
o Amino acid deamination
• Each can act as a source of Acetyl-CoA
• Acetyl-CoA is oxidised in the citric acid (Krebs) cycle
producing energy
THE CITRIC ACID CYCLE
• All air-breathing organisms use the citric acid cycle to
generate energy
• Several metabolic pathways deliver acetyl-CoA and
other intermediates for the cycle:
o Glycolysis of glucose via pyuvate to acetyl-CoA
o Fatty acid oxidation via acetyl-CoA
o Amino acid deamination via α-ketoacids
THE CITRIC ACID CYCLE
CH3
acetyl CoA C=O
SCoA
CO2C=O
CH2
CO2HOCH
CH2
CO2malate
CO2oxaloacetate
CO2-
CO2-
CH2
HO-C - CO2-
CH2
H - C - CO2-
CH2
CO2citrate
CO2
HO-CH
CO2-
CO2-
isocitrate
CH2
Two carbon atoms enter as acetyl-CoA
and are ejected as to CO2
CO2-
CO2-
CH
CH2
CH
CH2
CO2-
CO2fumarate
succinate
CO2-
CH2
C=O
CO2a-ketoglutarate
CH2
CH2
C=O
SCoA
succinyl CoA
CO2
ENERGY FROM GLUCOSE OXIDATION
• Three processes are involved
o Glycolysis of glucose to two pyruvate molecules
o Pyruvate oxidation to acetyl-CoA
o Oxidation of acetyl-CoA to CO2in the citric acid cycle
• Energy stored from oxidation of one molecule of glucose
= 36 ATP after all reduced coenzymes are reoxidised
GLYCOLYSIS OF GLUCOSE TO PYRUVATE
HC=O
HC-OH
HO-CH
HC-OH
HC-OH
CH2OH
HC=O
HC-OH
HO-CH
HC-OH
HC-OH
CH2O-P
glucose
glucose 6-phosphate
CH3
2 C=O
CO2pyruvate
CH2
2 C-O-P
CO2phosphoenolpyruvate
CH2OH
C=O
HO-CH
HC-OH
HC-OH
CH2O-P
CH2O-P
C=O
HO-CH
HC-OH
HC-OH
CH2O-P
CH2O-P
C=O
CH2OH
CH2O-P
HC-OH
fructose 6-phosphate
HC=O
fructose 1,6-bisphosphate
CH2OH
2 HC-O-P
CO22-phosphoglycerate
CH2O-P
2 HC-OH
CO23-phosphoglycerate
CH2O-P
2 HC-OH
CH2O-P
bisphosphoglycerate
Glycolysis of glucose yields 2 pyruvate + 2 ATP + 2 NADH
CONVERSION OF PYRUVATE TO ACETYL CoA
HSCoA + NAD+
CH3
C=O
CO2-
CO2 + NADH
CH3
C=O
SCoA
acetyl CoA
ACETYL CoA FROM OXIDATION OF FATTY ACIDS
n
CH3
(CH2)n
CH2
CH2
C=O
SCoA
CH3
(CH2)n
CH
CH
C=O
SCoA
n-2
CH3
(CH2)n
HC-OH
CH2
C=O
SCoA
CH3
(CH2)n
C=O
CH2
C=O
SCoA
CH3
(CH2)n
C=O
SCoA
CH3
C=O
SCoA
acetyl CoA
ACETYL CoA FROM GLUCOSE FOR FATTY
ACID SYNTHESIS
glucose
glycolysis
in cytosol
pyruvate
(cytosol)
pyruvate
(mitochondria)
acetyl CoA
(mitochondria)
oxaloacetate
CO2
CO2
acetyl CoA
in cytosol
malate
(cytosol)
oxaloacetate
(cytosoL)
citrate
(mitochondria)
citrate
(cytosol)
Fatty acid synthesis from acetyl CoA takes place in the cytosol
ACETYL CoA FROM GLUCOSE FOR FATTY
ACID SYNTHESIS
CO2
glucose glycolysis
(cytosol)
CH3
C=O
CO2-
pyruvate
(cytosol)
CO2
CH3
pyruvate
(mitochondria)
acetyl CoA
in cytosol
CO2-
HO-CH2
C=O
CH2
CH2
CO2-
CO2-
malate oxaloacetate
(cytosol)
(cytosol)
SCoA
acetyl CoA
(mitochondria)
oxaloacetate
CH3
C=O
SCoA
CO2-
C=O
CO2CH2
HO-C-CO2-
citrate
(cytosol)
CH2
CO2-
citrate
(mitochondria)
AMINO ACID METABOLISM
• Amino acids, from protein hydrolysis, can be deaminated
to form α-ketoacids
• Some α-ketoacids can be converted to pyruvate or to
other intermediates in the citric acid cycle for glucose
synthesis
• Others are converted into acetyl-CoA, used in fatty acid
synthesis
LIPID (FAT) SYNTHESIS
• Lipids (fats) are fatty acid esters of glycerol
• Fatty acids are synthesised by sequential addition of
two-carbon units to acetyl-CoA
• Acetyl CoA is derived from several sources, eg
glycolysis of glucose, from dietary carbohydrates
• Acetyl CoA is produced in the mitochondria but fatty acid
synthesis takes place in the cytosol
• Lipids are synthesised from fatty acids in adipose tissue
and in the liver
• Fatty acids for lipid synthesis can also arise from dietary
fats
FATTY ACID SYNTHESIS FROM ACETYL CoA
CO2-
CH3
C=O
SCoA
CH2
C=O
SCoA
R
acetyl CoA
growing fatty acid chain
CH2
malonyl CoA
CH2
CH2
C=O
R
CO2-
CH2
CH2
C=O
C=O
SACP
SACP
malonyl ACP
SACP
R
R
R
CH2
CH2
CH2
C=O
HC-OH
HC
CH2
CH2
HC
C=O
C=O
C=O
SACP
SACP
SACP
CHEMICAL CONTROLS
• Hormones are chemicals messengers released by a cell
or a gland in one part of the body that transmit
messages that affect cells in other parts of the organism.
• Important hormones in human metabolism include:
o Ghrelin - the hunger-stimulating hormone
o Leptin - the satiety (full-feeling) hormone
o Glucagon - the stored glucose releasing hormone
o Insulin - stimulates the formation of stored fat from
glucose
• Insulin and glucagon are part of a feedback system to
regulate blood glucose levels
• Leptin production is suppressed by abdominal fat.