Regulation by Covalent Modification Flashcards
Covalent modification
irreversibel changes in covalent structure (act by clevage)
reversible changes in cov structure = enzyme structures
- phos/ dephos
- methy/demeth
- ox/red
Other types -ADP-ribosylation -Adenylation -uridylation etc
non-covalent modificaiton
allosteric reg
Benifits of Regulation of enzyme activity via reversibvle covalent modification
Can occur inside a cell rev fast -enz cat -faster than controlling the absolute levels of enzymes (their synth/ degred)
amplification possible
controlled response
can integrate a variety of signals to provide an “intelligent response”
can result in the activation or inactivation of a more than one pathway to provide a multipronged response to a single signal
Types of reversible cov mod
phos adenlyation acetlylation myristoylation ubiquiotination ADP-riboslyation methylation ox/red of thiols
some are not functionally rev
Enzyme cycles
similar to “ substrate cycles” but the substrate is an enzyme
(a sub cycle is a futile cycle)
for ex with phos/ dephos
-> moreover the reactions themselves are enzyme cat
usually the enzymes catalysing the reactions are reciprocally regulated
active form of enzyme designated with an a subscript, and the inactive form is designated with a b subscript
can you tell if a covalently modified enzyme in the a or b form is phosphorylated
nope
can only tell that a is active
and b is inactive
groups that are usually phosphorylated
serine
theronine
tyrosine
Glycogen phosphyrlase
cat reaction of glycogen to G1P
has two important roles
1) mobalizing glycogen
2) inactivating glycogen synthesis
T state is inactive, and de-phos
=b
R state is active and phos
=a
on ser14
reciprocal regulation of glycogen phosphorylase
T => R is de-phopho to phospho
is triggered by glucagon (liver) and epinephrine (liver and the muscle)
R=>T by insulin phospho to de-phospho
activityof glycogen phophorylase is affected by the amount of enzyme in the active state
activity is thus depended on relative activities of kinase vs phophotase
reciphocally regulated - dependent of hormone signalling
I skipped a few slides see pictures
do it
Regualtion of Glycogen metabolism
nicely illustractes how several different pieces of information can be intergrate for an intelligent response
illulstrate several important aspects regarding the potential of regulation through covalent modification
Can allow cells/ tissues to respond to the needs of the organism
- hormonally regulated
- allosterically regulated, so the cell can respond to its own needs
- different tissues may have different responses like the liver and the muscle
Can allow coordinated response by several pathways
-phos dephos cascades
allows amplification
regulation of glycogen metabolism can allow coordinated responses by several pathways
phophotrotein phosphatase-1 can dephophorylate and thus activate ro deactivate several key regulatory enzymes
glycogen phophorylae kinase will also phophorylate and inactive glycogen synthase
note that allosteric effectors can override hormonal signals
note it
ADP ribosylation
covalent modification that is not reversible in practice
Bacteria ADP-ribosylating exotoxins
bAREs
covalently transfger and ADP ribose moity of NAD+ to target proteins of infected eukaryotes
AB cholera toxin
bARE A domain has ADP-ribosylation activity B domains (usually 5) are responsible for the translocation of the A-domain = enz across the cell membrane
activates adenylate cyclase and forms lots of cAMP and leads to cellular export of h2o, Na and Cl leading to diarrhea
Reversible covalent modificaiton
Redox
enzyme conformation and thus activity can be affected through the formation/ reduction of disulfide bonds
ex xanthine oxioreductase
Xanthine Oxioreductase (XOR)
an important enzyme inthe purine degradation pathway
uric acid is the end product of pruine metabolims in humans
- generally excreted int he urine
- if accumulates in thetissues causes medical problems like gout
emerging as a key enzyme involved in the response to oxidative stress
conversions between xanthine DH and xanthine oxidase
During anoxic conditions, AMP accumulated and leads to the conversion of xan DH to xan ox.
when oxic conditions resume, xan ox converts O2 to h2o2 and superoxide
common in diseased tissue
whats wrong with XD => XO
for example when blood supply is restricted (ishemia during a stroke or a heart attack or organ transplantation)
when blood flow resumes, post ischemic damage results from XOR
during ischemica ATP is used but nor produced, so AMP is built up
XD-> XO under anoxia, canno0t do much without an electron acceptor (no oxygen)
however, once blood flow resumes, O2 is converted to hydrogen peroxide and superoxide anions
Benificial roles of ROS
secondary messengers and combating infection
harmful roles of ROS
DNA damage
lipid oxidaation
ocidation of aa in protiens
inactivation of enzymes by oxidiozing their cofactors
Lipid oxidation
vulnerable to attack by radicles unsat lipids (PUFAs) are particularly vulnerable
formation of lipid radicles cause a chain reaaction: get degradation of the lipids and neioghboring lipids
In membranes:
perosidized tails of the lipids are more hydrophillic, try to migrate to the surface of the membrane
-> this disrupts the membranes structure and mades it leaky
vitamin E protects us!
Major pathways for ROS formation in vivo
NAD(P)H oxidase / mitochondrial ETC / XAN OX
superoxide disumatse
Fentoin reaction
XOR
see slides idk
