Lecture notes
Metabolism and Metabolic Regulation
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- The University Of Kent (UKC)
2nd Year BSc Biomedical Science Notes
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BI521 Metabolism and Metabolic RegulationPost-translational modifications as controllers of enzyme activities
Differential Phosphorylation in Metabolic Control
Regulation of PFK-1
Aspects of Metabolic Regulation
Aspects of Metabolic Regulation II
Aspects of Metabolic Regulation III
Plant Metabolism: Photosynthesis
Photosynthesis II
Photosynthesis III
Plant Metabolism: Calvin Cycle
Rubisco and Regulation
Photorespiration
C4 Photosynthesis
Crassulacean Acid Metabolism
Fate of The Photo-Assimilate
Microbial Metabolism in the Nitrogen Cycle
Microbial Response to Nitric Oxide
Metals in Bacterial Metabolism
Microbial Secondary Metabolites
Prokaryotic Genomics
Biotechnology and Biotransformations
Growth of Microorganisms
Growth of Microorganisms II
,Post-translational modifications as controllers of enzyme activities
- Many proteins are phosphorylated on their serine, threonine or tyrosine
residues. This is catalysed by protein kinases, Pi is removed.
- Acetylation of lysine residues neutralises proteins as lysine residues are
+vely charged, also changing the surface charge of the protein. Implicated
in the control of bacterial growth.
Protein kinase A
- Phosphorylates proteins that generate cellular energy – ATP
- Three subunits: catalytic, regulatory and anchoring AKAP.
- Kinases add phosphate groups while phosphatases remove them.
- PKA Is cAMP–dependent.
- PKA is inactive when cAMP is low, this results in a dimer forming between
2 out of 3 of the regulatory domains. Both catalytic domains bind to the dimer
and form an inactive complex.
- When [cAMP] and binds to its active site on the regulatory domains, the
subunits dissociate from the catalytic domains and PKA becomes active.
- To inactivate PKA, cAMP needs to be removed and this is done by
phosphodiesterases. These cleave cAMP to AMP, causing PKA to
inactivate and ATP–generating enzymes to stop.
- PKA: PKA phosphorylates proteins at their serine and threonine residues,
both in the cytoplasm and in the nucleus. Enzymes, ion channels (E.g.
cardiac muscle Ca2+ channels), chromosomal proteins (histones) and
transcription factors are all phosphorylated by PKA.
Phosphorylation
- Phosphate groups have a strong negative charge and are fairly bulky,
forming multiple hydrogen bonds. Phosphorylation may modify the shape of
flexibility of the protein chain or act as a readily-available recognition domain
for the other proteins.
AKAP
- A Kinase Anchoring Proteins; these target PKAs to particular locations in
the cell.
Differential Phosphorylation in Metabolic Control
- To control the flux of metabolites in a metabolic process, it is necessary to
regulate an irreversible step in the reaction. There is no sense in regulating
reversible reactions because the forward and reverse reaction are in
equilibrium, and so regulating this step would only slowdown the overall
metabolic processes, rather than controlling flux.
- Regulating an irreversible reaction will maintain or up-regulate one
metabolic process and, effectively, stop the other metabolic process. I.e
glycolysis and gluconeogenesis.
There are two pyruvate kinase genes:
- PKLR (abundant in liver)
, - PKM (abundant in muscle)
- These isoforms are similar in sequence, except that the liver/red blood cell
form has an N–terminal extension. Which includes a PKA recognition site in
a region of untranslated protein. This is so that they are easily accessible.
o R – R – X – S (Arg-arg-X-ser) is a PKA recognition motif that
influences the phosphorylation of the serine residue.
- The N–terminal extension increases the infinity for PEP.
o Pyruvate kinase is our glycolytic enzymes that catalyse the reaction
of PEP and ADP into ATP and pyruvate. It is a transfer of a
phosphoryl group from PEP to ATP. The liver isoform of PK is
responsible for GNG, as well as glycolysis and so regulation is
needed to ensure metabolites are not made and then consumed by
the other process, which would be futile and a waste of energy. PK
shows cooperativity with respect to PEP binding, activated by F16BP
and inhibited by ATP. Unlike the other isoforms of PK, the liver
isoform has an N-terminal domain that is phosphorylated on its serine
residue. This phosphorylation by a cAMP–dependent kinase
decreases the activity of PK. Its affinity for PEP decreases and the
hill coefficient increases. When F16BP is bound, PK becomes
hyperbolic with respect to PEP binding. Phosphorylation of PK does
not have a significant effect on Vmax but does shift the T/R
equilibrium toward the T state and increases cooperativity.
Remember, the phosphate group added to PKL is bulky and strongly
negative, and so the conformational change that ensues affects the
PEP binding site.
- Isoenzymes are different in that they possess motifs that enable them to be
post-translationally modified.
- PK is inhibited by acetyl CoA, long-chain FAs and alanine, which are signs
of ATP abundance.
- The quality of being phosphorylated is that you are sensitive to hormonal
regulation as kinases are influenced by cAMP.
Phosphofructokinase-1
- Catalyses the committed step of glycolysis.
- Inhibited by ATP, citrate and PEP. When ATP supply is abundant PEP
builds up and feedback and inhibits PFK1. When ATP supply is abundant
PEP builds up, feeds back and inhibits PFK1.
- Acetyl CoA and citrate signal that the TCA cycle is fully occupied, which
results in a slowing down of glycolysis and an increase in GNG.
Cooperativity
- You can’t plot cooperative enzyme data using the Michaelis-Menten
equation, use the hill equation.
- ‘n’ Is the hill number and is a measure of how cooperative and enzyme is.
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