CORSO DI BIOCHIMICA SISTEMATICA UMANA (ANNO 2006/07)
CORSO DI LAUREA IN BIOTECNOLOGIE
(I ANNO LAUREA SPECIALISTICA, INDIRIZZO MEDICO)
KNOWLEDGE OF METABOLIC PATHWAYS (FROM THE BIOCHEMISTRY COURSE)
Students are expected to have a good knowledge of the following metabolic pathways:
Glycolysis/gluconeogenesis
Tricarboxylic acid cycle
Pentose phosphate shunt
Respiratory chain
Heme synthesis
Cholesterol synthesis (farnesyl, geranyl)
Sketch of AA metabolism (essential, chetogenetic, gluconeogenetic)
Urea synthesis, transaminases
Knowledge doesn’t include the ability to draw formulas of the single molecules involved in
the pathway but:
Starting molecules and their source (diet, blood, specific organs, etc)
Final products and their release (CO2, urea, lactate etc.)
By products: ATP, NADH, NADPH and their possible use (e.g. NADPH: fatty acid
synthesis, deoxy ribonucleotides etc.)
Mechanism of the in/out movement of molecules from the cells (pumps, antiports,
simports, etc.)
Nutrients: oxygen, fatty acids, glucose, AA.
Cofactors: vitamin and metal ions
List of all the molecules involved in every metabolic pathway (e.g. glycolysis: glucose,
ATP, NAD, phosphate, Mg)
Role of enzymes: they increase the reaction rate, not the direction. The direction of a
chemical reaction depends on ∆G0 and ∆G (local concentration of substrates).
THE COURSE
SHARED PROPERTIES OF LIVING ORGANISMS
DISSIPATIVE:
life takes place only in environments with an excess of energy: in our case, in the
sunlight. This concept includes the following facts:

Cells have to feed continuously

Cells have to breath continuously

Cells cannot ever stop producing energy

Cells use energy to keep many ionic gradients (Ca++, Na+, K+, Cl- etc.)
Gradients are necessary for most cell functions (signal transduction, glucose and
AA transport, etc.)
EVOLUTIONARY:
formation of evolutionary trees for any molecule and organism mediated by
irreversible bifurcation followed by selection. The driving forces of bifurcation and
selection depend on the environment and can be considered “local”.
CYCLIC:
at any level from the molecules to the species, precise feedback mechanisms can
be identified that regulate the number of the objects involved in the equilibrium.
OSCILLATING:
in any self-regulatory cyclic system the number of any item is changing in time with
a periodicity that depends on the size of the system – from seconds for chemical
reactions to years for prey/predator relationships – and the time the feedback
signals need to diffuse across the system.
COMPETITIVE:
as biological systems tend to expand exponentially in a finite environment, they
become – sooner or later – limited in their growth due to a shortage in some
essential factor (“nutrient”). The competition for the limiting nutrient will locally drive
the selection.
Concept of “essential” nutrient
Metal ions (Zn, Cu, Fe, Se)
Inorganic phosphate
Selected aminoacids
Vitamins (why eating vitamins is better than producing them by themselves)
CELL BEHAVIORS
30.000 genes how many behaviours?
Only 4/5 different behaviours
Primary behaviour:
PROLIFERATION (unicellular organisms)
Secondary behaviour:
DIFFERENTIATION
One genome many tissues
The difference depends on local conditions
PROLIFERATION
Local supply of all the essential nutrients
Uptake of nutrients
 Movement in the direction of nutrient
 Type of nutrients (proteins versus aminoacids, stomach and endocytosis)
 Digestion of the nutrients
 Determinants of feeding rate (CD71, GLUT1, Na+/H+ antiporter)
 Differences of nutrient carriers (GLUT1/GLUT4) according to
proliferation/differentiation
 Metastases, lymphocytes homing
Nutrients and signals
 Chemotactic factors (angiogenesis)
DIFFERENTIATION
Local deficiency of some of the essential nutrients leads to specific forms of differentiation,
depending on the functions of the lacking nutrient (iron, essential aminoacids, PUFA).
Factors affecting nutrients local supply (blood flow, angiogenesis, vessel permeability,
cells competition in a closed environment).
Stem cells, niches, embriogenesis
NUTRIENTS and SIGNALS
Difference between nutrients and signals
Nutrients are required for a chemical reactions (substrates or cofactors) whose rate is
dependent on their presence
Signals regulate the reaction rate giving (how???) some information concerning the
availability of nutrients (T3/T4 oxygen, insulin  glucose etc.)
As a matter of fact the whole metabolism is always and only (???) regulated by its own
substrates either directly or through signals.
SIGNAL TRANSDUCTION (ST)
Definition of Sign and Signal
We call signals all (physical or chemical) events able to transmit information to a cell.
Signaling requires at least two components:

a physical (e.g. sound) or chemical (e.g. hormone) event that it is released into the
environment in specific conditions and that we can call a sign (S)

a cellular structure able to react with (S) modifying the cell behavior according to
the concentration and direction of (S). These structures are called Receptors (R).
(S) n are classified as sound, light, hormones, cytokines, chemokines, growth factors, and
so on, according to their major effect, but they share a common property: the ability to give
information about the existence of specific environments or about the availability of one or
more nutrients. The minimal information content carried by any sign is that all the
conditions required for its synthesis are present. But also Receptors (R) are synthesized in
specific conditions and therefore carry the information that this conditions exist.
To make signal understandable to the cell a set of chemical events called signal
transduction take place upon binding of the ligand (S) to its receptor.
Non-linearity of signal transduction: ST is a multi-step process with different checkpoints
sensitive to different external factors (inositol  NADH/NAD+  ethanol; oxygen, diet, Gproteis and miristoyl and farnesyl, etc)
SIGNALLING
SIGNAL: SIGN + receptor + second messengers

SIGN : information content of molecules or physical events (ionic gradients eg)

Receptors: subunits, localization, induction

SIGNAL TRANSDUCTION
Second messengers
o Ions (asymmetry)
o ATP dependent
o GTP dependent
Linear chains and networks in SIGNALLING
Non linearity of SIGNALS spreading
METABOLISM
Energetics of living systems
The role of environment (nutrients, pO2 etc.)
Factors affecting the direction of metabolic pathways
what task the enzymes have been selected for?
To increase the reaction rate
Why should we need to increase the reaction rate (competition)
What tell us the enzyme Km for specific substrate
The time arrow in dissipative systems
metabolism in differentiated cells
cell cycle
COFACTORS SHARED BY DIFFERENT METABOLIC PATHWAYS
(working as limiting nutrients)
ATP/ADP
 cAMP
GTP/GDP
 cGMP
 G proteins
 Reactions driven by GTP
NAD+/NADH




Ethanol (-)
Fatty acids (-)
Oxygen and respiratory chain (+)
Glucose and glucogenetic aminoacids (+)
NADP+/NADPH




Fatty acids synthesis (+)
Ribonucleotides reduction (RNA DNA) (+)
GSSG reduction (+)
Sorbitol synthesis (+)
 Hexose monophosphate shunt (-)