Metabolism is the sum of all chemical reactions in the cell
The pathways have dedicated purposes:
o extraction of energy
o storage of fuels
o synthesis of important building blocks
o elimination of waste materials
The pathways can be represented as a map:
o follow the fate of metabolites and building blocks
o identify enzymes that act on these metabolites
o identify points and agents of regulation
o identify sources of metabolic diseases
Catabolic pathways- break down molecules to produce chemical energy
Anabolic pathways- use energy to convert small molecules into macromolecules
How do cows make milk that is high in fat?
Catabolic pathways break cellulose down into small metabolites such
as pyruvate, lactate and succinate
Precursors for anabolic pathways
Anabolic pathways then use these to form lipids
Catabolic and anabolic pathways are connected by intermediate
metabolites
This is done in the cow stomach
The lipids will then go into the milk
Reciprocal Regulation
Most cells have enzymes to carry out both degradation and synthesis of key biomolecules
e.g. glucose (glycolysis and gluconeogenesis)
Simultaneous synthesis and degradation would be wasteful- no net gain and loss of energy
Prevented by reciprocal regulation of opposing pathways- when one is active the opposite
pathway in unactive
Would not be possible if both pathways catalyzed by exactly the same enzymes
At least one step catalyzed by different enzymes in the catabolic and anabolic directions –
regulated separately- points of regulation
Opposing catabolic and anabolic pathways may also occur in different subcellular
compartments- e.g. fatty acids synthesis occurs in the cytosol while fatty acids degradation
occurs in the mitochondria
, Key points
The flow of metabolites through the pathways is regulated to maintain homeostasis.
Homeostasis occurs when concentrations of metabolites are kept at a steady state in the
body.
When perturbed, a new steady state is achieved.
Sometimes, the levels of required metabolites must be altered very rapidly.
need to increase the capacity of glycolysis during action
need to reduce the capacity of glycolysis after the action
need to increase the capacity of gluconeogenesis after successful action
Levels of regulation
Rates of a biochemical reactions depend on many factors that could impact either activity of
enzyme or concentration of effector:
Activity of the enzyme
concentration of the enzyme
rate of translation versus rate of degradation
intrinsic activity of the enzyme
could depend on substrate concentration, effectors, or covalent modifications e.g.
phosphorylation
Concentrations of effectors
allosteric regulators
competing substrates
pH, ionic environment
Factors determining enzyme activity
10 mechanisms by which
enzyme activity can be
controlled
1 – 5 change the concentration
of the enzyme
This involves the transcription of
enzyme, the stability of enzyme
mRNA and the rate of translation
(provides a way of storing mRNA
that can be activated via
translation)
7 – 10 change the activity of the
enzyme
This involves amount of substrate, allosteric effectors, covalent modifications and
interactions with regulatory proteins
General concepts of metabolic integration
Single pathway can be regulated at multiple steps by different mechanisms- Refined
summative control (ESSAY)
E.g. glycolysis and gluconeogenesis
, Multiple regulatory mechanisms target a single protein
E.g. glucokinase can be regulated by transcription, mRNA stability, degradation,
compartmentation and allosterically
This can be advantageous for
efficient regulation (if you method fails there are more methods capable of ensuring
regulation occurs)
for integration of different signals (for e.g. one signal might alter transcription and another
regulating allosteric regulation- more enzyme and more activity)
amplification of response (both activity and concentration can allow response amplification)
Time scale of response (some mechanisms such as transcription will have a long term change
and other such as allosteric modification will have a short term change)
Control of one protein can have secondary actions- Increasing the concentration of one
enzyme will increase the concentration of product that can have an effect on other enzymes
by for instance, allosteric activation or inhibition (e.g. increase transcription of L-type
pyruvate kinase by insulin will increase pyruvate product that will activate pyruvate
dehydrogenase)
Regulation by extracellular signals
Hormones- Carried in the bloodstream from endocrine gland (e.g. pancreas) to target cells
or organs (e.g. liver)
They bring about changes in target cell
Change in transcription of genes encoding metabolic enzymes
Altered activity of existing enzyme
Multiple regulatory effects by a single hormone helps coordination
Regulated protein degradation
Once synthesized protein molecules have finite lifetime
Rate of degradation differs from one enzyme to another
Liver enzymes: <1 hour - > 1 week
Degradation can be regulated to alter enzyme concentration
Example: reductase (cholesterol biosynthesis) controlled by protein degradation
Compartmentalisation
Movement of metabolites between compartments can also be a point of regulation- e.g.
movement of glucose from outside the cell to the cytosol where it can get metabolized
Glucokinase regulatory protein sequesters hexokinase IV (glucokinase) in the nucleus (ePBL)
It phosphorylates glucose and therefore is only active in the cytosol but under certain
conditions it can be moved into the nucleus to inhibit it
Reaction rate depends on substrate concentration
Rate more sensitive to substrate concentration at low concentrations.
o Frequency of substrate meeting the enzyme is limiting
Rate becomes insensitive at high substrate concentrations.
o The enzyme is nearly saturated with substrate
When [substrate] << Km, reaction rate depends on [substrate]
o If Km is greater than physiological [substrate], changes in [substrate] will alter
reaction rate
, Many enzymes have Km near or greater than the physiological concentration of substrate
Allosteric regulation of enzyme activity
Allosteric effectors or modulators are generally small molecules
Allosteric effectors can be activators or inhibitors
Bind non-covalently to specific regulatory site that is different to the active-site
E.g. ATP
Covalent modification of enzymes alter their activity
Phosphorylation is catalyzed by protein kinases
Dephosphorylation is catalyzed by protein phosphatases (can be spontaneous)
Specific amino acids are phosphorylated
Phosphate group alters properties e.g. structure leading to change in activity
E.g. phosphorylation in amino acids side chains can change the structure of enzymes
significantly that will change how they recognise co-factors and substrates
Regulatory proteins can regulate enzyme activities
Binding of regulatory protein subunits can affect specificity
E.g. phosphoprotein phosphatase 2A (PP2A)
Recognizes several substrate proteins- wide specificity
Specificity is determined by regulatory subunit
Creates unique substrate binding site – conferring specificity
Coordination and integration of metabolic pathways
Important to think about them within the cell but also between different organs and tissues
ATP and AMP are key cellular regulators allowing coordination on both levels
Cellular concentration of ATP typically 5mM
A 10% decrease in [ATP] can greatly affect the activity of ATP utilizing enzymes
Mechanisms to respond to cellular [ATP]
o ATP is an allosteric regulator of many enzymes
A 10% decrease in [ATP] leads to a dramatic increase in [AMP]
o AMP can be a more potent allosteric regulator
AMP activates AMP dependent protein kinase (AMPK)
Activated by increased cellular [AMP] if:
o Reduced nutrient supply
o Increased exercise
o Acts as an ‘energy sensor’
Phosphorylates many metabolic enzymes
o Shifts metabolism away from energy consuming
processes
o Increases energy generating catabolic pathways
o Stimulates feeding behavior
o Coordinated change
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