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Overview of Protein Catabolism
Proteases are zymogens
Excess amino acids are not stored
Normal protein turnover 1-2% of body protein per day
~75-80% amino acids reused; lose 30-40 g/day
Not excreted as amino acids or ammonia
Protein(diet)
stomach/intestine
Aamino acids Protein
(body)
B
CD urea
cycle
Nitrogensecretion
.
.
Methods of Nitrogen Excretion
• Uricotelic (birds, reptiles)
• Ammonotelic (fish)
• Ureotelic (mammals)
Two Amino Acids are Used to Transport Nitrogen
• Transaminase• Nonspecific for one
pair, specific for the other pair– Pyr-Ala– KG-Glu
are the two most common
-amino acid
-amino acid'
-keto acid
-keto acid'
transaminase
PLP
H3N C
CO2
CH2
H
CH2
CO2
H3N C
CO2
CH2
H
CH2
CO NH2
NH4
Glutamine Synthetase
H2OMg2+
ATP ADP+Pi
.
.
• Gln synthetase particularly important to the brain
Transamination Mechanism
N
PO43-
CH3
HO
CHN
H
Enz-Lys
H
C CO2R
NH3
H
N
PO43-
CH3
HO
CH
NH
C CO2R
H
H
Enz-Lys NH3
N
PO43-
CH3
HO
CH2
NH3
C CO2R
O
N
PO43-
CH3
HO
CH
NH
C CO2R
H
N
PO43-
CH3
HO
CH
NH
C CO2R
HH
N
PO43-
CH3
HO
CH2
NH
C CO2R
HH2O
H
Urea Cycle
Importancemeans of excreting nitrogen in nontoxic form
LocationMitochondrial matrix and cytoplasm of liver and kidney
ReactionsEnergeticsRegulation
Intracellular Ammonium Generation
• Glutaminase mitochondria only• Liver quantitatively more important
H3N C
CO2
CH2
H
CH2
CO2
H3N C
CO2
CH2
H
CH2
CO NH2
NH4
Glutaminase
H2O
• Oxidative deamination of Glu Only• Glu DH can use NAD or NADP
H3N C
CO2
CH2
H
CH2
CO2
C
CO2
CH2
CH2
CO2
O
ATP, GTP, NADHADP
NH4
Glutamate dehydrogenase
H2O
NAD(P)H
+ H+NAD(P)+
.
.
Carbamoyl Phosphate Synthetase I
• Liver Mitochondrial enzyme• RDS of urea cycle• Activated by (requires) NAcGlu
.
.
carbamoylphosphate
C
O
NH2 OPO32-
NH4 2 ATP 2 ADP+ 1 Pi
carbamoyl phosphatesynthetase I
HCO3Mg2+
Ornithine Transcarbamoylase
• Mitochondrial enzyme• Transported to Cp after synthesis
.
.
Pi
ornithinetranscarbamoylase
carbamoylphosphateC
O
NH2 OPO32-
H3N C
H
CH2
CO2
CH2
CH2
NH3
L-ornithine
H3N C
H
CH2
CO2
CH2
CH2
NH C NH2
O
L-citrulline
Arginosuccinate Synthetase
• Cytoplasmic enzyme
.
H3N C
H
CH2
CO2
CH2
CH2
NH C NH2
O
citrulline
.
ATP AMP+ PPi H2O
arginosuccinatesynthetase
Asp
CNH3 H
CO2
CH2
CO2
H3N C
H
CH2
CO2
CH2
CH2
NH
CHN NH C H
CO2
CH2
CO2arginosuccinate
Mg2+
Arginosuccinase
• Enzyme restricted to liver and kidney• Fumarate converted back to Asp
.
.
H3N C
H
CH2
CO2
CH2
CH2
NH
CHN NH C H
CO2
CH2
CO2arginosuccinate
H3N C
H
CH2
CO2
CH2
CH2
NH
CH2N NH2
arginosuccinase
fumarate
C H
CO2
C
CO2
H
Arginase
• Primarily liver enzyme• Ornithine transported back into mitochondrion by
ornithine-citrulline antiporter
.
.
H3N C
H
CH2
CO2
CH2
CH2
NH
CH2N NH2
H3N C
H
CH2
CO2
CH2
CH2
NH3
arginase
H2O
C
O
NH2H2Nurea
Regulation
• GluNAc as described earlier occurs by changing ATP affinity
• 10-20–fold change in enzyme levels based on “nitrogen balance” i.e. how much protein is consumed relative to needs
EnergeticsFalse Claim #27 of Vegetarians
• “consuming protein uses energy”
• 4 ATP equivalents consumed in the urea cycle
• However, the carbon backbone is now available for energy use
• Carnivores obtain large amount of energy from amino acid carbon, herbivores ~10-15%
Carbon Backbone Catabolism
• Glucogenic amino acids vs. ketogenic amino acids
• Glucogenic are converted to metabolite of glycolysis (e.g., pyruvate) and can be converted into glucose
• Ketogenic form molecules such as acetoacetate, which can be converted to fat
• Most amino acids are glucogenic and ketogenic• Leu is the sole amino acid which is ketogenic
Ala
-keto acid' -amino acid'
PLP
Transaminase
to glycolysis
CO2
C O
CH3
pyruvate
CO2
C H
CH3
H3N
Ala
Gln, Glu
H3N C
CO2
CH2
H
CH2
CO2
H3N C
CO2
CH2
H
CH2
CO NH2
NH4
Glutaminase
H2O -keto acid'-amino acid'
PLP
Transaminase C
CO2
CH2
CH2
CO2
Oto Kreb's cycle
Asn, Asp
-keto acid'-amino acid'
PLP
TransaminaseH3N C
CO2
CH2
H
CO2
H3N C
CO2
CH2
H
CO NH2
NH4
Asparaginase
H2O
C
CO2
CH2
CO2
O to Kreb's cycle
Thr, Ser, GlyCO2
C H
CH
H3N
CH3
OH
Ser hydroxymethyltransferase
PLP
CO2
C H
H
H3NCO2 and NH4
+
MeTHF
THF
H2OSer hydroxymethyl
transferase
CO2
C H
CH2OH
H3N
Ser dehydratasePLP
THF MeTHF
NAD+ NADH+ H+
major p/w: Gly synthase
pyruvate to glycolysisCO2 C
O
CH3
NH4+
CH3CHO
Pro
N
CO2H
H
CH2
CH2
C
C
O
CO2
HH3N
H
Glu--semialdehyde
1. Pro dehydrogenase2. spontaneous
NAD+
NADH+ H+
Glu--semialdehyde DH
NADH+ H+
NAD+
CH2
CH2
CO2
C
CO2
HH3N
.
.
Met
H3N C
CH2
CH2
S
CH3
CO2
H
Met adenosyltransferase
ATP PPi + Pi
H3N C
CH2
CH2
S
CH3 O
CH2
OHHO
NN
N N
NH2
CO2
H
S-Adenosylmethinonine (SAM)
Acceptor methylated acceptor
SAM SAH
SAH
H2O Adenosine
H3N C
CH2
CH2
CO2
H
SH
homocysteine
3 steps
CoASH
Ser CO2 + NH4+
2 NAD 2 NADH
proprionyl CoA
Arg
CH2
CH2
C
C
O
CO2
HH3N
H
Glu--semialdehyde
-keto acid' -amino acid'
PLP
TransaminaseH3N C
H
CH2
CO2
CH2
CH2
NH
CH2N NH2
H3N C
H
CH2
CO2
CH2
CH2
NH3
arginase
H2O
C
O
NH2H2Nurea
.
.
Phe
CO2
C H
CH2
H3N
CO2
C H
CH2
H3N
OH
Phe Hydroxylase
O2 H2O
NADNADH+ H
.
.
Glu TAase
PLP
KG Glu
CO2
C O
CH2
OH
Cu2+
ascorbateO2 CO2
Dioxygenase
HO
OH
CH2
CO2
homogentisate
1,2-Dioxygenase
O2HO
OH
CH2
CO2
homogentisate
C O
CH2
CH
C
CH
CH2
O
CO2
CO2
maleylacetoacetate
C O
CH2
CH
C
C
CH2
O
CO2
CO2
H
fumerylacetoacetate
cis-trans isomerase hydrolase
H2O
C
CO2
C
H
CO2
H
acetoacetateCH3
C
CH2
O
CO2
thiolase
CoASH
acetate andacetyl CoA
Phenylketonuria (PKU) is a Congenital Absence of Phe
Hydroxylase CO2
C H
CH2
H3N
Phe Hydroxylaseabsent
O2 H2O
NADNADH+ H
.
CO2
C O
CH2
LeuCO2
C H
CH2
H3N
CH
CH3
CH3
Leu
CO2
C O
CH2
CH
CH3
CH3
-ketoisocaproate isovaleryl CoA
C O
CH2
CH
CH3
CH3
S-CoAGlu TAase
PLP
-KG Glu
ß-methylcrotonyl CoA
C O
CH
CH
CH3
CH3
S-CoAbranched-chainamino acid DH
PLP
NAD NADH+ H
ß-methylglutaconyl CoA
C O
CH
CH
CH2
CH3
S-CoA
CO2
ß-hydroxy-ß-methylglutaryl CoA(HMG-CoA)
CH3
CH2
CO2
C O
S-CoA
C
HO C
-keto aciddehydrogenase
CoASH CO2
crotonase
Mg2+
ATP ADP+ Pi
CO2
biotinhydrating enzyme
H2O
HMG-CoA lyase
acetoacetate
C
CH2
CO2
CH3
O
C O
CH3
S-CoA
Acetyl-CoA
Maple Syrup Urine Disease
• The result of branched chain amino acid dehydrogenase deficiency
• Oxidation products of keto compounds accumulate
CO2
C H
CH2
H3N
CH
CH3
CH3
Leu
CO2
C O
CH2
CH
CH3
CH3
-ketoisocaproate isovaleryl CoA
C O
CH2
CH
CH3
CH3
S-CoAGlu TAase
PLP
-KG Glu
branched-chainamino acid DH
PLP
NAD NADH+ H
-keto aciddehydrogenase
CoASH CO2
HistidineCO2
C H
CH2
H3N
N NH
CO2
C H
C
N NH
H
urocanate
Histidase
NH4
CO2
CH2
CH2
N NH
O
4-Imidazolone-5-propionate
urocanase
H2O
Imidazolonepropionatehydrolase
H2O
CO2CH2CH2CHCO2
HN NH2
N-Formiminoglutamate (Figlu)
H3N C
CO2
CH2
H
CH2
CO2
THFN5-formiminoTHF
glutamateformiminotransferase
Cysteine Has Two Catabolic Pathways
H3N C
CO2
CH2SH
H C
CO2
CH2SH
O
mercaptopyruvate
sulfurtransferase
2H H2S
C
CO2
CH3
O
pyruvate
cysteinedioxygenase
[O]
H3N C
CO2
CH2SH
H
transaminase
-ketoacid
-aminoacid
PLP
transaminase
-ketoacid
-aminoacid
PLPH3N C
CO2
CH2SO2
H
cysteinesulfinate
ß-sulfinylpyruvate
C
CO2
CH2SO2
Odesulfinase
SO32-
C
CO2
CH3
O
pyruvate