MBChB

Integration of Mammalian
Metabolism

Mrs Mlambo
Office 160 B
Biochemistry Department
University of Zimbabwe
 Integration of Metabolism
• Protein Biosynthesis
• Carbohydrate Biosynthesis
• Lipid Biosynthesis
• Biosynthesis of Phosphoglycerides and Triacylglycerols
• Terpene Biosynthesis
• Steroid Biosynthesis
• Nucleotide Biosynthesis
The Metabolic Map
 Overview of Metabolic Pathways
• The most important metabolic pathways include glycolysis, the citric acid
cycle, the pentose phosphate pathway, gluconeogenesis, and glycogen
synthesis & degradation.
• Glycolysis is regulated to perform its two roles:
– 1. The conversion of glucose into pyruvate as part of ATP generation
– 2. To serve as a source of biosynthetic precursors.

• A high level of ATP switches off phosphofructokinase, indicating that

cellular energy needs are being met.

• A high level of citrate also switches off phosphofructokinase, indicating

that the need for biosynthetic precursors is being met.
 Overview of Metabolic Pathways
• Glycolysis is also deactivated by decreasing levels of F-2,6-BP in
the liver, a change triggered in the liver by glucagon when blood
glucose is low.
• In the citric acid cycle, fuel enters as acetyl CoA.
• Oxidation is followed by chemiosmosis.
• The citric acid cycle provides many intermediates for biosynthesis.
• The pentose phosphate pathway is important for the generation of
NADPH for reductive biosynthesis and the formation of ribose 5-
phosphate for nucleotide synthesis.
 Metabolic Crossroads

• The most important metabolic crossroads: glucose 6-phosphate,

pyruvate, & acetyl CoA.
• Glucose 6-phosphate: results from the phosphorylation of intercellular glucose.
– One of the following then occurs: glycogen synthesis, glycolysis, or formation of ribose 5-
phosphate for the pentose phosphate pathway.
– Liver and kidneys possess G6P, which enables glucose to be released into the blood.

• Pyruvate: interconverts with lactic acid to shift metabolic burden from muscle to
liver.
– Pyruvate may be transaminated to alanine.
– May be carboxylated to oxaloacetate then to phosphoenolpyruvate then to glucose 6-
phosphate in gluconeogenesis.
– Pyruvate can be oxidatively decarboxylated to acetyl CoA, which is irreversible,
committing the pathway to the citric acid cycle or to the synthesis of lipids.

• Acetyl CoA: is formed by oxidative decarboxylation of pyruvate and the β-

oxidation of fatty acids.
– Either completely oxidized in the citric acid cycle or taken up in the biosynthesis of
cholesterol, ketone bodies (for transporting acyl units), or citrate for fatty acid synthesis.
 Cellular Perspectives on Metabolic Integration
• The compartmentalization of the eukaryotic cell by
semipermeable membranes is a major factor in metabolic
control.

• Glycolysis, the pentose phosphate pathway, and fatty acid

synthesis take place in the cytosol.

• Fatty acid oxidation, the citric acid cycle and oxidative

phosphorylation take place in the mitochondria.
 Physiological Perspectives on Metabolism
• The pathways of metabolic energy conversion are different within
different tissues.
• Brain: has only glucose for fuel, except during starvation when ketone
bodies may be utilized, which minimizes protein breakdown.
• Muscle: has large glycogen stores (75% of body's glycogen supply), where
pyruvate formed in glycolysis is converted to lactate or alanine and
exported to the liver for gluconeogenesis.
– In resting muscle, ketone bodies (like acetoacetate) are a primary fuel.
• Adipose tissue: specialized for the interconversion of fatty acids and
triacylglycerols
– But to form the glycerol 3-phosphate needed for triacylglycerol synthesis, adipose
cells need glucose.
– In the reverse pathway within adipose tissue, cyclic AMP activates the breakdown
of triglycerides to fatty acids and glycerol.
 Physiological Perspectives on Metabolism
• Liver: the first destination of most substances absorbed by the intestine.
– Liver is a major control center for both glucose and lipid metabolism.
– Fatty acids can either become incorporated into triglycerides and phospholipids or they
can be converted into ketone bodies for use as fuel.

• Hormones: Insulin, glucagon, epinephrine and norepinephrine are important

hormones in metabolic control.
– Insulin and glucagon are the most important regulators of fuel metabolism.
– Insulin signals the fed state. Insulin stimulates glycogen synthesis. Suppresses
gluconeogenesis. Stimulates glycolysis in the liver (primarily for building blocks). Enables
transport of glucose into muscle and adipose tissue, and of certain amino acids into
muscle tissue.
– Glucagon is released in response to low blood sugar and targets the liver. Glucagon
inhibits glycogen synthesis. Inhibits fatty acid synthesis. Stimulates gluconeogenesis.
Blocks glycolysis in liver (preventing the formation of precursors).
Highlights of Metabolism
1. ATP = universal energy currency
•Expended to ensure unidirectionality of each metabolic
pathway and complete conversion to products

•An important allosteric regulator

•Generated by the oxidation of fuel molecules: NADH and
FADH2 shuttle electrons to the ETC where the bulk of ATP is
formed via oxidative phosphorylation.
2. NADPH is the major electron donor in
reductive biosynthesis
•formed primarily via the pentose phosphate pathway

3. Central metabolic pathways have both

anabolic and catabolic roles.
•TCA is an excellent example of an amphibolic pathway.
 Carbs, Amino Acids

Fats, Amino Acids

Amino Acids

•TCA is an excellent example of an amphibolic pathway.

4. Distinct pathways for biosynthesis and
degradation

•Ensures favorable thermodynamics for both directions

•Separate, but interrelated, control mechanisms (often the 1st

step)

•Compartmentalization (e.g., cytosol vs. mitochondrial matrix)

5. Many coenzymes

coenzyme role example

Niacin/B3 (NAD+) redox malate dehydrogenase
Riboflavin/B2 (FAD) redox succinate dehydrogenase
Pantothenic acid/B5 (CoA) acyl transfer pyruvate dehydrogenase
Pyridoxal phosphate/B6 transamination -KG --> Glu
Vitamin B12 rearrangements homocysteine--> Met
Thiamine/B1 (TPP) decarboxylation pyruvate dehydrogenase
Biotin/B7 CO2 carrier pyruvate carboxylase
Lipoic acid acyl carrier pyruvate dehydrogenase
Folic Acid/B9 carbon carrier amino acid degradation
6. Several molecules act as metabolic junction points.

glucose-6-phosphate

glycogen pyruvate ribose-5-P

pyruvate

acetyl-CoA lactate alanine OA

acetyl-CoA

hormones fatty acids ketone bodies

7. A defect in a single enzyme of metabolism can
be disastrous.

•Lack of an essential metabolite?

•Build-up of a toxic metabolite?
8. Tissues & organs are specialized.
 8. Tissues & organs are specialized.
• Maintainers supply fuel for
the consumers.

 Maintainers: liver and

Brain

adipose tissue
 Consumers: skeletal Fuel
muscles, heart, brain
•Interactions between tissues and
organs are mediated by hormone
signals carried via bloodstream.
Metabolic Interrelationships
Liver- #1 metabolic player
•Responds quickly to dietary conditions because of rapid turnover
of its enzymes
•Processes most incoming nutrients

•Maintains constant concentrations of nutrients in blood (e.g.,

via gluconeogenesis), smoothing out fluctuations due to the
Starve-Feed Cycle
•Processes toxins and wastes (e.g., through urea cycle)

•Synthesizes and secretes plasma proteins

Liver- #1 metabolic player

•Primarily depends on b-
oxidation of fatty acids for
its own energy needs.
Liver
•Amino acids go directly to the
liver through the portal vein after
absorption.
•Uses them to make proteins, for
gluconeogenesis, for biosynthesis
of nitrogen-containing molecules,
or for fuel.
Adipose Tissue- maintainer #2
•Stores triglycerides and releases FA’s and glycerol
as signaled by glucagon/ epinephrine

•Turnover is 50-60 g/day.

cAMP-activated
triglycerides fatty acids + glycerol
lipases

transport in blood Albumin

muscle heart liver

•Two distinct types:
white adipose tissue and
brown adipose tissue.
•Brown fat has high
levels of thermogenin,
which are metabolically
activated by cold
exposure.
•BAT has more
capillaries than WAT
Skeletal Muscle (big consumer)

• Long strenuous exercise can lead to:

• Lactic acid build up!
• Depleted fat stores!
• Decreased blood sugar!
• Carnitine deficiency!
Energy Systems of Skeletal Muscle

(Phosphagen system)
Anaerobic Conditions- bursts of
heavy activity
• ATP exhausted rapidly (1 or 2 sec); replenished by:

Phosphagen System
Anaerobic Conditions- bursts of
heavy activity
•phosphocreatine lasts ~10 seconds

•next 1 to 2 minutes
glycogen -> G-6P -> pyruvate -> lactate
Fate of Lactate
•Cooperation between
muscle and liver (Cori
cycle) to regenerate
glucose from lactate.
•Heart also burns lactate.
Lactate Threshold

• With low intensity work, lactate is cleared from the

bloodstream as fast as it is made.
• As work increases, there is a point when lactate is produced
too fast for the body to clear it.

Exercise cannot be sustained

for more than a minute or two
after lactate threshold because
of PFK-1 inhibition

work
Aerobic Conditions- rest, slow
runs, light activity
1. glycogen -> G-6P -> pyruvate -> CO2 + H2O
•1- 2 hour supply, moderately fast
•Limited by entry of pyruvate into mitochondria and/or O2 supply

2. fatty acids -> acetyl-CoA -> CO2 + H2O

•Many hours supply, slow
•Limited by diffusion of FA’s from blood, carnitine
Brain
•No significant energy reserves.

•Dependent on blood glucose at ~4.5 mM to maintain ion

gradients.

•Uses 20% of the total O2 consumed by a resting human (only

2% of the body mass)

•After several days of low glucose, switches to use of ketone

bodies, which are degraded via TCA. Conserves body ’ s
proteins.
 Heart
Cardiac muscle is aerobic only
with circulating fats the preferred
fuel.

Lack of O2 leads to tissue

death (myocardial infarction).
Hormones
1. Insulin (high blood sugar)

•Insulin deficiency or resistance can lead to hyperglycemia,

metabolic syndrome, and diabetes.
The insulin receptor is a receptor tyrosine kinase
(RTK).
Insulin binding triggers auto- phosphorylation at Tyr.
2. Epinephrine (fight or flight)
3. Glucagon (low blood
sugar)