Classes of organisms based on Nutrition

Energy/carbon
Energy /carbon classes of organisms
Week 7-8

CARBOHYDRATE
METABOLISM
 Basic Concepts

Definitions
Metabolism: The processes of catabolism and
anabolism
Catabolism: The processes by which a living
organism obtains its energy and raw materials
from nutrients
Anabolism: The processes by which energy
and raw materials are used to build
macromolecules and cellular structures
(biosynthesis)
Overview of Metabolism
ANIMAL METABOLISM
 Overview of glucose metabolism in selected cell types

Glucose
No mitochondria
Glucose
Glucose

Glucose The Full

Glycogen Monty
Lactate
Stage 1 postparandial
All tissues utilize glucose

Stage 2 postabsorptive
KEY Maintain blood glucose
Glycogenolysis
Glucogneogenesis
Lactate
Pyruvate
Glycerol
AA
Propionate
Spare glucose by metabolizing fat

Stage 3- Early starvation

Gluconeogenesis

Stave 4 Intermediate starvation

gluconeogenesis
Ketone bodies

Stage 5 Starvation
Carbohydrate Metabolism/ Utilization-
Utilization-
Tissue Specificity

Muscle cardiac and skeletal

Oxidize glucose/produce and store glycogen (fed)

Breakdown glycogen (fasted state)

Shift to other fuels in fasting state (fatty acids)

Adipose and liver

Glucose
acetyl CoA

Glucose to glycerol for triglyceride synthesis

Liver releases glucose for other tissues

Nervous system

Always use glucose except during extreme fasts

Reproductive tract/mammary

Glucose required by fetus

Lactose
major milk carbohydrate

Red blood cells

No mitochondria

Oxidize glucose to lactate

Lactate returned to liver for Gluconeogenesis
 Glicolysis

Glycolysis is a series of reactions that takes place in the
cytoplasm of all prokaryotes and eukaryotes

a molecule of glucose is degraded in a series of enzyme-
catalyzed reactions to yield two molecules of the three-
carbon compound pyruvate

Also called Embden Mayerhoff metabolism

Aerobic (glucose
pyruvate) and anaerobic (glucose

lactate)

Fermentation (glucose
ethanol)
Three possible catabolic fates of the pyruvate formed in
glycolysis..
glycolysis
An Overview: Glycolysis Has Two Phases

Glycolysis is tightly regulated in coordination
with other energy-yielding pathways to assure a
steady supply of ATP.
Hexokinase, PFK-1, and pyruvate kinase are all
subject to allosteric regulation that controls the flow
of carbon through the pathway and maintains
constant levels of metabolic intermediates.
Entry of glycogen, starch, disaccharides, and hexoses into the
preparatory stage of glycolysis
Fates of Pyruvate under Anaerobic
Conditions: Fermentation

The NADH formed in glycolysis must be

recycled to regenerate NAD, which is required
as an electron acceptor in the first step of the
payoff phase. Under aerobic conditions,
electrons pass from NADH to O2 in
mitochondrial respiration.
Pyruvate is the terminal electron acceptor in Lactic Acid
Fermentation

Under anaerobic or
hypoxic conditions,
many organisms
regenerate NAD by
transferring electrons
from NADH to
pyruvate, forming
lactate
Ethanol Is the Reduced Product in Ethanol Fermentation

Other organisms, such as

yeast, regenerate NAD
by reducing pyruvate to
ethanol and CO2.

In these anaerobic
processes
(fermentations), there is
no net oxidation or
reduction of the carbons
of glucose.
Gluconeogenesis

Gluconeogenesis is the
pathway for glucose
synthesis from
noncarbohydrate
precursors

Important for the maintenance of blood glucose levels
during starvation or during vigorous exercise.

The brain and erythrocytes depend almost entirely on
blood glucose as an energy source.

Gluconeogenesis occurs mainly in the liver and to a
lesser extent in the kidney.

Most enzymes of gluconeogenesis are cytosolic, but
pyruvate carboxylase and glucose 6-phosphatase are
located in the mitochondrial matrix and bound to the
smooth endoplasmic reticulum, respectively.
The Pathway of Gluconeogenesis

Seven of the steps in

gluconeogenesis are catalyzed by
the same enzymes used in glycolysis;
these are the reversible reactions.

Three irreversible steps in the
glycolytic pathway are bypassed by
reactions catalyzed by
gluconeogenic enzymes:
conversion of pyruvate to PEP via
oxaloacetate, catalyzed by pyruvate
carboxylase and PEP carboxykinase;
dephosphorylation of fructose 1,6-
bisphosphate by FBPase-1; and
dephosphorylation of glucose 6-
phosphate by glucose 6-phosphatase.
Alternative paths from pyruvate to phosphoenolpyruvate

Conversion of mitochondrial
pyruvate to cytosolic
phosphoenolpyruvate to
initiate gluconeogenesis.

Oxaloacetate cannot pass
across the inner
mitochondrial membrane, so
it is reduced to malate, which
can do so.

The initial irreversible step of glycolysis is bypassed by
glucose 6-phosphatase, which catalyzes the
dephosphorylation of glucose 6-phosphate to
form glucose
This enzyme is mainly found in liver and kidney, the only two
organs capable of releasing free glucose into the blood.
A special transporter (GLUT2) in the membranes of these
organs allows release of the glucose.

Glycolysis and gluconeogenesis are reciprocally
regulated to prevent wasteful operation of both
pathways at the same time.
 The Cori Cycle

During vigorous exercise, pyruvate produced by glycolysis in muscle is

converted to lactate by lactate dehydrogenase.

The lactate diffuses into the bloodstream and is carried to the liver.

Here it is converted to glucose by gluconeogenesis.The glucose is
released into the bloodstream and becomes available for uptake by
muscle (as well as other tissues, including brain).
 Pentose Phosphate Patway

The pentose phosphate pathway (PPP), also called
the hexose monophosphate shunt, is an alternate
pathway of glucose metabolism that supplies the
NADPH required by many biosynthetic pathways.
The main purpose of the PPP is to generate NADPH to be
used in pathways for synthesis of important molecules,
eg, amino acids, lipids, and nucleotides.
NADPH derived from the PPP is also important for
detoxification of reactive oxygen species.
The PPP also is responsible for synthesis of ribose 5-
phosphate for nucleotide biosynthesis

The PPP operates in two phases: an oxidative phase
and a nonoxidative phase
 Glycogen Metabolism

Glycogen is stored in muscle and liver as
large particles.

Contained within the particles are the
enzymes that metabolize glycogen, as well
as regulatory enzymes

Glycogen
granules in a
hepatocyte
glycogenolysis

the catabolic pathways from glycogen to glucose 6-phosphate

Catalyzed by glycogen phosphorylase
Glycogen synthesis
A glycogen chain is elongated by
glycogen synthase. The enzyme
transfers the glucose residue of
UDP-glucose to the nonreducing end
of a glycogen branch to make a new
(-1
4) linkage
Branch synthesis in glycogen

The glycogen-branching enzyme (also called amylo (1
4) to (1
6)

transglycosylase or glycosyl-(4
6)-transferase) forms a new branch
point during glycogen synthesis
Glycogen degradation and glycogen synthesis are
reciprocally regulated by hormones.
Kinases and phosphatases control the activities of the
interconvertible enzymes glycogen phosphorylase and glycogen
synthase
Week 6-7

LIPID AND
CHOLESTEROL
METABOLISM
Lipid Transport
Fatty acids are activated and transported into
Mitochondria

Fatty acid entry into mitochondria via the acyl-

acyl-carnitine
carnitine//
carnitine transporter
OXIDATION OF FATTY
ACIDS
Stages of fatty acid
oxidation
The -oxidation
pathway
Oxidation of a monounsaturated fatty acid
 Oxidation of a
polyunsaturated fatty acid
Oxidation of propionyl-
propionyl-
CoA produced by oxidation
of odd-
odd-number fatty acids
Coordinated regulation of fatty acid synthesis and
breakdown.
Comparison of oxidation in mitochondria and in
peroxisomes and glyoxysomes
 Ketone Bodies

Ketone bodies, formed in the liver, are exported to

other organs as fuel

Overproduced in Diabetes and during Starvation

The compound of ketone bodies:
Formation of ketone
bodies from acetyl-CoA
D--Hydroxybutyrate as a fuel
Ketone bodies formation and export from liver
BIOSYNTHESIS OF
FATTY ACIDS
Fatty Acid Biosynthesis
 Not exactly the reverse of degradation
by a different set of enzymes , in a different part of the cell
 Primarily in the cytoplasm of the following tissues:
liver, kidney, adipose, central nervous system and
lactating mammary gland
 Rule: Fatty acid biosynthesis is a stepwise assembly of
acetyl-CoA units (mostly as malonyl-CoA) ending with
palmitate (C16 saturated)
 3 Phase: Activation, Elongation,Termination
Liver is the major organ for fatty
acid synthesis
Fatty Acid Biosynthesis
Synthesis Beta Oxidation

Cytosol
Mitochondria

Requires NADPH
NADH, FADH2

Acyl carrier protein
CoA

D-isomer
L-isomer

CO2 activation
No CO2

Keto saturated
Saturated keto
The acetyl-CoA carboxylase reaction
ACTIVATION Cofactor
O Biotin

CH3C~SCoA HN NH
O
ATP HCO3- CH2CH2CH2CH2CO
S NHCH2CH2CH2CH2 ENZYME
LYS
ADP + Pi Biocytin
-OOC-CH
2C~SCoA
CO2
O
O
O
C N NH
O
active carbon CH2CH2CH2CH2CO
S
Acetyl-CoA carboxylase Carboxybiocytin
Acyl Carrier Protein

Phosphopantetheine
H H HO CH3 O
HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-CH2-Ser- ACP
O OH H O
Cysteamine

Acyl carrier protein

10 kDa

H H HO CH3 O O
HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-P-O-CH2 Adenine
O
O OH H O O
O H

Coenzyme A O-P-O OH
OH
Initiation
Overall Reaction
Malonyl-CoA + ACP

CH3C~SCoA -OOC-CH
2C~S- ACP + HS-CoA
O O Acyl Carrier
CO2 HS-CoA Protein

CH3C- CH2C~S- ACP

O O

NOTE:
Malonyl-CoA carbons become new COOH end
Nascent chain remains tethered to ACP
CO2, HS-CoA are released at each condensation
 -Carbon Elongation
CH3C- CH2C~S- ACP

O Reduction
O
NADPH
-Ketoacyl-ACP reductase
H
D isomer
CH3C- CH2C~S- ACP

HO O Dehydration
-H2O -Hydroxyacyl-ACP dehydrase
H
CH3C- = C- C~S- ACP
H Reduction
NADPH O
Enoyl-ACP reductase

CH3CH2CH2C~S- ACP

O
 TERMINATION Ketoacyl ACP
Synthase
Transfer to Malonyl-CoA -KS
Transfer to KS
-S-ACP
-CH2CH2CH2C~S- ACP

O Free to bind
Split out CO2 Malonyl-CoA
CO2

When C16 stage is reached, instead of transferring to KS,

the transfer is to H2O and the fatty acid is released
Acetyl-CoA is delivered to cytosol from the
mitochondria as CITRATE
 O
O-C-R
O
 Fatty acyl-CoA
R-C-O
 DHAP reduction to glycerol-PO4 O
or O-C-R
 Glycerol kinase to glycerol-PO4
 Two esterifications
 Diacylglycerol-PO4 intermediate
 Triacylglycerol
Metabolism of Phospholipids

Strategy of Glycerophospholipid
Biosynthesis
Activate diacylglycerol
Activate appending moiety (salvage
NH2
N

O N

PPP- Ribose

CTP
Eukaryotes 1 ATP
2 Glycerol-3-PO4 Glycerol
DHAP
FA-CoA
O
1-Acyl-DHAP
CH2O-C-R Phosphatidic acid
O
NADPH 3
R-C-O-C-H
1-Acyl-glycerol-3-PO4 DAG
CH2OP ATP
CTP
CDP-diacylglycerol

O Pi ethanolamine (CDP-ethanolamine)

CH2O-C-R choline (CDP-choline)

O
Serine (phosphatidylethanolamine)
R-C-O-C-H
Glycerol (CDP-diacylglycerol)
CH2OH
Inositol (CDP-diacylglycerol)
1,2 DAG
Cardiolipin (phosphatidylglycerol)
Metabolism of Cholesterols
 Sources of Cholesterol

Cholesterol synthesized
Diet De novo synthesis in extrahepatic tissues

Liver cholesterol
pool

Secretion of HDL Free cholesterol Conversion to

and VLDL In bile bile salts/acids
 Cholesterol Synthesis

80 % in liver, ~10% intestine, ~5% skin

Occurs in cytosol

Requires 18Acetyl-CoA16NADPH
36ATP

Similar to ketogenic pathway

Highly regulated
Cholesterol
Synthesis
Cholesterol and cholesteryl esters are carried in the blood
as plasma lipoproteins

Lipoprotein and lipid transport