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An Overview of

Metabolism

Metabolism

Metabolism is all the chemical reactions that


occur in an organism
Cellular metabolism

Cells break down excess carbohydrates first, then


lipids, finally amino acids if energy needs are not
met by carbohydrates and fat
Nutrients not used for energy are used to build up
structure, are stored, or they are excreted
40% of the energy released in catabolism is
captured in ATP, the rest is released as heat

Anabolism

Performance of structural
maintenance and repairs
Support of growth
Production of secretions
Building of nutrient reserves

Catabolism

Breakdown of nutrients to
provide energy (in the form of
ATP) for body processes

Nutrients directly absorbed


Stored nutrients

Cells and Mitochondria

Cells provide small organic


molecules to mitochondria
Mitochondria produce ATP
used to perform cellular
functions

Carbohydrate Metabolism

Primarily glucose

All cells can utilize glucose for energy production

Fructose and galactose enter the pathways at various points


Glucose uptake from blood to cells usually mediated by
insulin and transporters

Liver is central site for carbohydrate metabolism

Glucose uptake independent of insulin


The only exporter of glucose

Blood Glucose
Homeostasis

Several cell types prefer glucose as


energy source (ex., CNS)
80-100 mg/dl is normal range of blood
glucose in non-ruminant animals
45-65 mg/dl is normal range of blood
glucose in ruminant animals
Uses of glucose:
Energy source for cells
Muscle glycogen
Fat synthesis if in excess of needs

Fates of Glucose

Fed state

Storage as glycogen

Storage as lipids

Liver
Skeletal muscle
Adipose tissue

Fasted state

Metabolized for energy


New glucose synthesized

Synthesis
Synthesis and
and
breakdown
breakdown occur
occur
at
at all
all times
times
regardless
regardless of
of
state...
state...
The
The relative
relative rates
rates
of
of synthesis
synthesis and
and
breakdown
breakdown

High Blood
Glucose
Pancreas

Muscle
Glucose
absorbed

Insulin:
Glucago
n

Adipose
Cells
Glucose
absorbed

Glycogen
Glucose
absorbed

immediately after eating a meal

Glucose Metabolism

Four major metabolic pathways:


Immediate source of energy
Pentophosphate pathway
Glycogen synthesis in liver/muscle
Precursor for triacylglycerol synthesis

Energy status of body regulates which


pathway gets energy
Same in ruminants and non-ruminants

Fate of Absorbed Glucose

1st Priority: glycogen storage

2nd Priority: provide energy

Stored in muscle and liver


Oxidized to ATP

3rd Priority: stored as fat

Only excess glucose


Stored as triglycerides in adipose

Glucose
Utilization
Adipose

Energy
Stores

Glycogen

Glucose
Pentose
Phosphate
Pathway

Ribose-5-phosphate

Glycolysis

Pyruvate

Glucose
Utilization
Adipose

Energy
Stores

Glycogen

Glucose
Pentose
Phosphate
Pathway

Ribose-5-phosphate

Glycolysis

Pyruvate

Glycolysis

Sequence of reactions that


converts glucose into pyruvate
Relatively small amount of energy produced
Glycolysis reactions occur in cytoplasm
Does not require oxygen
Lactate (anaerobic)

Glucose Pyruvate
Acetyl-CoA (TCA cycle)

Glycolysi
s
Glucose + 2 ADP + 2 Pi
2 Lactate + 2 ATP + 2 H2O

Adenosine Tri-Phosphate (ATP)

Link between energy releasing and


energy requiring mechanisms

rechargeable battery

ADP + P + Energy

ATP

Mechanisms of ATP Formation

Substrate-level phosphorylation

Substrate transfers a phosphate group


directly
Requires enzymes
Phosphocreatine + ADP
Creatine + ATP

Oxidative phosphorylation

Method by which most ATP formed


Substrate transfers electrons to
transporter which enters the electron
transport chain

First Reaction of Glycolysis

Traps glucose in cells (irreversible in muscle cells)


Hexokinase is used by most plants, animals,
and microbes to phosphorylate glucose
Glucokinase in hepatic tissue
Cows do not have hexokinase

Glycolysis - Summary
2 ATP

Glucos
e
4 ADP

2
ADP

4 ATP
2
NAD
2 NADH + H

2 Pyruvate

Pyruvate Metabolism

Three fates of pyruvate:

Conversion to lactate (anaerobic)


Conversion to alanine (amino acid)
Entry into the TCA cycle via pyruvate
dehydrogenase pathway

Pyruvate Metabolism

Three fates of pyruvate:

Conversion to lactate (anaerobic)


Conversion to alanine (amino acid)
Entry into the TCA cycle via pyruvate
dehydrogenase pathway

Anaerobic
Metabolism of
Pyruvate
Problem:

During glycolysis, NADH is formed from


NAD+
Without O2, NADH cannot be oxidized to
NAD+
No more NAD+

All converted to NADH

Without NAD+, glycolysis stops

Anaerobic
Metabolism of
Solution:
Pyruvate

Turn NADH back to NAD+ by making lactate


(reduced)
(oxidized)
(lactic acid)
NADH+H+

NAD+

COO
C

CH3
Pyruvate
(oxidized)

COO
Lactatedehydrogenase

HC

OH

CH3
Lactate

(reduced)

Anaerobic
Metabolism of
Pyruvate
ATP
yield

Two ATPs (net) are produced


in the anaerobic breakdown of one
glucose

The 2 NADHs are used to reduce 2


pyruvate
to 2 lactate

Reaction is fast and doesnt require


oxygen

Pyruvate Metabolism Anaerobic


Lactate Dehydrogenase

Pyruvate

Lactate
NADH

NAD+

Lactate can be transported by blood to liver and


used in gluconeogenesis

Cori Cycle
Lactate is
converted to
pyruvate in the liver

Pyruvate Metabolism

Three fates of pyruvate:

Conversion to lactate (anaerobic)


Conversion to alanine (amino acid)
Entry into the TCA cycle via pyruvate
dehydrogenase pathway

Pyruvate metabolism

Convert to alanine and export to blood


Glutamate

Ketoglutarate

COO
C

CH 3
Pyruvate

Keto acid

COO
Alanineaminotransferase
(AAT)

HC

NH 3+

CH 3
Alanine

Amino acid

Pyruvate Metabolism

Three fates of pyruvate:

Conversion to lactate (anaerobic)


Conversion to alanine (amino acid)
Entry into the TCA cycle via pyruvate
dehydrogenase pathway

Pyruvate Dehydrogenase
Complex (PDH)

Prepares pyruvate to enter the TCA cycle

Aerobic Conditions
Electron
Transpor
t Chain

TCA
Cycle

PDH - Summary
Pyruvat
e
2
NAD
2 NADH + H
CO2

Acetyl
CoA

TCA Cycle

In aerobic conditions TCA cycle links


pyruvate to oxidative phosphorylation
Occurs in mitochondria
Generates 90% of energy released from
feed

Metabolizes carbohydrate, protein, and fat

Strategy is to oxidize acetyl-CoA to CO2 and


capture energy as NADH(FADH2) and ATP

TCA Cycle Summary


Acetyl
CoA

1 ATP

3
NAD

1
ADP

3 NADH +
H

1 FAD
1 FADH2

Oxidative
Phosphorylation

Oxidative Phosphorylation
and the Electron Transport
System

Requires coenzymes (NAD and


FAD) as H+ carriers and consumes
oxygen
Key reactions take place in the
electron transport system (ETS)

Cytochromes of the ETS pass H2s to


oxygen, forming water

The basic chemical reaction is:


2 H 2 + O2 2

Oxidation and Electron


Transport

Oxidation of nutrients releases


stored energy

Feed donates H+
H+s transferred to co-substrate

NAD+ + 2H+ + 2eFAD + 2H+ + 2e-

NADH + H+
FADH2

So, What Goes to the


ETS???
From each molecule of glucose entering
glycolysis:
1.
2.

3.

From glycolysis: 2 NADH


From the TCA preparation step (pyruvate to acetyl-CoA): 2
NADH
From TCA cycle (TCA) : 6 NADH and 2 FADH 2

TOTAL: 10 NADH + 2 FADH2

Electron Transport Chain

NADH + H+ and FADH2 enter ETC

Travel through complexes I IV

H+ flow through ETC and eventually


attach to O2 forming water

NADH + H+
FADH2

3 ATP
2 ATP

Electron Transport Chain

Total ATP from Glucose

Anaerobic glycolysis 2 ATP + 2


NADH
Aerobic metabolism glycolysis +
TCA
31 ATP from 1 glucose molecule

Volatile Fatty Acids

Produced by bacteria in the fermentation of


pyruvate
Provides important energy sources for animals,
particularly ruminants or those that rely on
cellulose as a key carbohydrate in their diet
Three major VFAs

Acetate

Propionate

Energy source and for fatty acid synthesis


Used to make glucose through gluconeogenesis

Butyrate

Energy source and for fatty acid synthesis


Some use and metabolism (alterations) by rumen wall and
liver before being available to other tissues

Use of VFA for Energy

Enter TCA cycle to be oxidized

Acetic acid

Propionic acid

Yields 10 ATP
Yields 18 ATP

Butyric acid

Yields 27 ATP
Little butyrate enters blood

Utilization of VFA in
Metabolism
Acetate
Energy
Carbon source for fatty acids
Adipose
Mammary gland

Not used for net synthesis of glucose

Propionate
Energy
Precursor of glucose

Butyrate
Energy
Carbon source for fatty acids - mammary

Effect of VFA on Endocrine


System
Propionate
Increases blood glucose
Stimulates release of insulin
Butyrate
Not used for synthesis of glucose
Stimulates release of insulin
Stimulates release of glucagon
Increases blood glucose
Acetate
Not used for synthesis of glucose
Does not stimulate release of insulin
Glucose
Stimulates release of insulin

Oxidation and Electron


Transport

Oxidation of nutrients releases


stored energy

Feed donates H+
H+s transferred to co-substrate

NAD+ + 2H+ + 2eFAD + 2H+ + 2e-

NADH + H+
FADH2

Oxidative
Phosphorylation

A BRIEF INTERLUDE

Need More Energy (More


ATP)??

Working animals

Increase carbon to oxidize

Increased kidney size, glomerular filtration rate

Increased ability to deliver oxygen to tissues and get rid of


carbon dioxide

Increased liver size and blood flow to liver

Increased ability to excrete waste products

Increased gut size relative to body size


Increased feed intake
Increased digestive enzyme production

Increased ability to process nutrients

Horses, dogs, dairy cattle, hummingbirds!

Lung size and efficiency increases


Heart size increases and cardiac output increases
Increase capillary density

Increased ability to oxidize small carbon chains

Increased numbers of mitochondria in cells


Locate mitochondria closer to cell walls (oxygen is lipid-soluble)

Hummingbirds

Lung oxygen diffusing ability 8.5 times


greater than mammals of similar body
size
Heart is 2 times larger than predicted for
body size
Cardiac output is 5 times the body mass
per minute
Capillary density up to 6 times greater
than expected

Rate of ATP Production


(Fastest to Slowest)

Substrate-level phosphorylation

Glucose

Pyruvate

Lactate

Aerobic carbohydrate metabolism

Creatine + ATP

Anaerobic glycolysis

Phosphocreatine + ADP

Glucose

Pyruvate

CO2 and H2O

Aerobic lipid metabolism

Fatty Acid

Acetate

CO2 and H2O

Potential Amount of Energy


Produced
Aerobic lipid metabolism
Fatty Acid for
Acetate
CO2 and H2O
(Capacity
ATP Production)

Aerobic carbohydrate metabolism

Pyruvate

CO2 and H2O

Anaerobic glycolysis

Glucose
Glucose

Pyruvate

Lactate

Substrate-level phosphorylation

Phosphocreatine + ADP

Creatine + ATP

Glucose
Utilization
Adipose

Energy
Stores

Glycogen

Glucose
Pentose
Phosphate
Pathway

Ribose-5-phosphate

Glycolysis

Pyruvate

Pentose Phosphate Pathway

Secondary metabolism of glucose

Produces NADPH

Similar to NADH
Required for fatty acid synthesis

Generates essential pentoses

Ribose
Used for synthesis of nucleic acids

Pentose Phosphate Pathway


Glucose6phosphat
e

6Phosphogluconolactone

6Phosphogluconate
D-Ribulose5phosphate

RNA or
DNA

D-Ribose5phosphate

Glucose
Utilization
Adipose

Energy
Stores

Glycogen

Glucose
Pentose
Phosphate
Pathway

Ribose-5-phosphate

Glycolysis

Pyruvate

Energy Storage

Energy from excess carbohydrates


(glucose) stored as lipids in adipose
tissue
Acetyl-CoA (from TCA cycle) shunted to
fatty acid synthesis in times of energy
excess

Determined by ATP:ADP ratios

High ATP, acetyl-CoA goes to fatty acid synthesis


Low ATP, acetyl CoA enters TCA cycle to generate
MORE ATP

Glucose
Utilization
Adipose

Energy
Stores

Glycogen
Glycogenesi
s

Glucose
Pentose
Phosphate
Pathway

Ribose-5-phosphate

Glycolysis

Pyruvate

Glycogenes
is

Liver

710% of wet weight


Use glycogen to export glucose to the
bloodstream when blood sugar is low
Glycogen stores are depleted after
approximately 24 hrs of fasting (in
humans)
De novo synthesis of glucose for
glycogen

Glycogenesis

Skeletal muscle

1% of wet weight

More muscle than liver, therefore more


glycogen in muscle, overall

Use glycogen (i.e., glucose) for energy


only (no export of glucose to blood)
Use already-made glucose for
synthesis of glycogen

Fates of Glucose

Fed state

Storage as glycogen

Storage as lipids

Liver
Skeletal muscle
Adipose tissue

Fasted state

Metabolized for energy


New glucose synthesized

Synthesis
Synthesis and
and
breakdown
breakdown occur
occur
at
at all
all times
times
regardless
regardless of
of
state...
state...
The
The relative
relative rates
rates
of
of synthesis
synthesis and
and
breakdown
breakdown

Gluconeogenesis

Necessary process

Glucose is an important fuel

Central nervous system


Red blood cells

Not simply a reversal of glycolysis


Insulin and glucagon are primary
regulators

Gluconeogenesis

Vital for certain animals

Ruminant species and other pre-gastric


fermenters

Convert carbohydrate to VFA in rumen

Feline species

Little glucose absorbed from small intestine


VFA can not fuel CNS and RBC

Diet consists primarily of fat and protein


Little to no glucose absorbed

Glucose conservation and gluconeogenesis


are vital to survival

Fasting Situation in NonRuminants

Where does required glucose come


from?

Breakdown or mobilization of glycogen stored by glucagon


Glycogenolysi
Glucagon - hormone secreted by pancreas during times of fas
s

Mobilization of fat stores stimulated by glucagon and epineph


Triglyceride = glycerol + 3 free fatty acids
Lipolysis
Glycerol can be used as a glucose precursor

The breakdown of muscle protein with release of amino acids


Alanine can be used as a glucose precursor

Proteolysis

Low Blood
Glucose
Pancreas

Muscle
Proteins Broken
Down

Insulin:
Glucago
n

Glycogen
Glucose released

Adipose
Cells
Glycerol, fatty acids
released

In a fasted state, substrates for glucose


synthesis (gluconeogenesis) are released
from storage

Gluconeogenesis

Synthesis of glucose from noncarbohydrate precursors during fasting in


monogastrics
Glycerol

Amino acids
Lactate
Supply carbon skeleton
Pyruvate
Propionate
There is no glucose synthesis from fatty acids

Occurs primarily in liver, but can also occur


in kidneys and small intestine

Carbohydrate Comparison

Primary energy substrate


MOST monogastrics = glucose
Ruminant/pre-gastric fermenters = VF

Primary substrate for fat synthesis


MOST monogastrics = glucose
Ruminant = acetate

Extent of glucose absorption from gut


MOST monogastrics = extensive
Ruminant = little to none

Carbohydrate Comparison

Cellular demand for glucose


Nonruminant = high
Ruminant = high

Importance of gluconeogenesis
MOST monogastrics = less important
Ruminant = very important

Ketone production
MOST monogastrics = abnormal
situation