Protein Breakdown - most rapidly degraded enzymes occupy metabolic control

points; N-terminal Asp, Arg, Leu, Lys, Phe degraded rapidly;Ala, Gly, Met, Ser,Val - degraded slowly
Mechanisms of breakdown
-in lysosomes; many proteases, pH 5
-targeted breakdown - ubiquitin + proteasomes

Ub-activating enzyme

76 residue protein

C-terminal thioester

Ub-conjugating enzymes:
Thioester exchange

if you break them down in 8, they are easy to digest

Ub-protein ligase:
in full protein strucutres, they are really compact amine displacement
peptidases of thioester
amino proteasome e
acids ~8 residue peptides
 in the yeast proteosome, the beta subunits which are shown are all proteases - cavities are for proteises

The Yeast
Proteosome

-4 stacked rings; abba: 7 subunits per ring; only -type subunits have enzymatic activity; (700 kDa)
- -type subunits not identical to one another - therefore confer large range of specificities
for cleavage of peptide bonds in proteins; (red) bound protease inhibitor molecules - line
hydrolysis chamber of proteosome. The bacterial ClpP protease, pictured below, is structurally
homologous to the eukaryotic -type subunits everything happens within a proteosome

bacterial
ClpP
protease

Top view Side view

Amino Acid Catabolism

Thiamine pyrophosphate catalyzed reactions: carbanion character of

thiamine, decarboxylation of a-ketoacids, group transfer reactions of
ketones (transketolases)
Biotin catalyzed reactions: CO2 carrier in carboxylation reactions
Lipoic Acid catalyzed reactions; acyl transfer, redox
Coenzyme B12 catalyzed reactions; free radical, carbon chain
rearrangements
Pyridoxal phosphate: transamination, racemization, decarboxylation,
others
Tetrahydrofolic acid: one carbon transfer, multiple oxidation states
S-Adenosyl methionine: methyl transfer
NAD(P)/NAD(P)H two electron redox reactions
FAD(FMN)/FADH2(FMNH2) one and two electron redox reactions
PLP is the key coenzyme in amino acid catabolism

Enzyme-bound form

shchiff base formation

Transamination reactions are catalyzed by PLP

Amine donor Amine acceptor

exchange of amine and keto function

fully reversible reaction

can also decarboxylate amino acids

NH3,
Amine acceptor Amine donor Urea cycle
PLP-catalyzed Transamination (also racemization)- Part 1

Proton
removal
(Ha)

OH- attack

H+
addn
PLP-catalyzed Transamination (also racemization)- Part 2

to regenerate you have to run the reaction in reverse

Oxidative deamination and the Urea cycle

amonium is toxic, so you have to get rid of it through urea cycle

 cofactor involved is biotin

Urea cycle

________________
Overall reaction

________________

NAD

NADH

oxaloacetate
 Urea Cycle
Step 1

Step 3

Step 4 a, b elimination
H O

-O
O-
Arginine + fumarate
O NH O

+
HN N O-
H

NH 3+
Argininosuccinate
PLP catalyzes other aa reactions: Electron pair Decarboxylation
overlap determines course of reaction

can provide
binding sites
which make
different
things
parallel to
each other -
RCH2NH2 + CO2
depending
on what
enzyme
were talking
about, a
different
bond lines
up with the Dehydration of serine
pi system
of the
Similarly, Cys breaks down to H2S and pyruvate
peridoxal H+ removal; like start of deamination
system

Side chain cleavage

Thr

CH3CHO + Gly
acetaldehyde
how does it know if
tis decarboxylase
or deaminase? or
if you have polar
Similarly, Ser breaks atoms (like serine)
could break a lot of
down to HCHO + Gly different bonds
youre breaking
formaldehyde electron density
into electron
density but if you
break CC bond
then you arent
THF: tetrahydrofolic acid - a pterin

Redox
reagent
THF - 1 C transfer

H2C(O)
Overall Fuel
Metabolism
How can the events in space and time which take
place within the spatial boundary of a living
organism be accounted for by physics and
chemistry?

Erwin Schrdinger, What is Life?