Transcript Document
BIOC 460 DR. TISCHLER LECTURE 38 AMINO ACID DEGRADATION/ UREA CYCLE
OBJECTIVES
1.
Describe transaminase , and glutamate dehydrogenase reactions; discuss their roles in the removal of nitrogen waste in the body.
2.
In relation to the urea cycle : a) describe the carbamoyl phosphate synthetase I and ornithine transcarbamoylase reactions b) identify direct sources of nitrogen for the urea cycle c) describe roles of acetylglutamate and arginine in regulation of the cycle 3.
In relation to hyperammonemia a) define the term b) discuss why a defect in either carbamoyl phosphate synthetase I or ornithine transcarbamoylase causes this problem c) explain how excess ammonia might cause an energy deficit in brain cells.
OBJECTIVES (cont.)
4.
List the key endproduct(s) for catabolism of each of the following amino acids: alanine; aspartate; glutamate; glutamine; isoleucine; leucine; phenylalanine; tyrosine; valine 5.
For phenylalanine hydroxylase : a) describe the reaction b) explain its relationship to phenylketonuria ; c) describe unusual side reactions of excess phenylalanine d) discuss why an individual may be mentally retarded if the enzyme is lacking
-Amino acid
NH HOOC-CH-R -Keto acid
O
2 HOOC-C-R
O
HOOC-C-CH 2 CH 2 COOH
-Ketoglutarate Cofactor = pyridoxal phosphate Glutamate NH 2 HOOC-CH-CH 2 CH 2 COOH Figure 1. Depiction of a general transamination (aminotransferase) reaction. The
-amino acid other than glutamate can be a wide variety
Aspartate aminotransferase (glutamate-oxaloacetate transaminase) NH 2 Aspartate HOOC-CH-CH 2 COOH +
-ketoglutarate
O
Oxaloacetate HOOC-C-CH 2 COOH + glutamate Alanine aminotransferase (glutamate-pyruvate transaminase) + NH 2 HOOC-CH-CH
Alanine 3 -ketoglutarate
O
Pyruvate HOOC-C-CH 3 + glutamate Figure 2. The reactions catalyzed by aspartate aminotransferase and alanine aminotransferase.
-Ketoglutarate + NH 4 +
Glutamate dehydrogenase
NADH NAD + Glutamate NH 3 + ATP
Glutamine synthetase
ADP + P i Glutamine Figure 3. In non-hepatic tissues the linked reactions of glutamate dehydrogenase and glutamine synthetase remove two ammonia molecules from the tissues as a way of ridding the tissues of nitrogen waste. The glutamine deposits the ammonia in the kidney for excretion.
-Amino acid
-Ketoglutarate Aminotransferase Glu NADH + NH 4 4 + + dehydrogenase Urea cycle UREA
-Keto acid NAD + + H 2 O Figure 4. In liver, nitrogen waste from amino acids ends up in urea. Amino acids are derived either from the breakdown of protein in various tissues or from what is synthesized in those tissues
Fumarate
(returns to TCA cycle)
Arginine
Argininosuccinate AMP+PP i
O UREA H 2 N C NH 2 Citrulline
-
Aspartate
OOC-CH
NH 3 +
CH 2 COO -
ATP CYTOPLASM
argininosuccinate synthetase
2ATP + H
CO 3 + NH
4 +
argininosuccinase
Carbamoyl phosphate synthetase
Ornithine 2ADP + P i Carbamoyl phosphate
Ornithine transcarbamoylase Citrulline P i MITOCHONDRIA
arginase Figure 5. Carbamoyl phosphate synthetase reaction and the urea cycle. Overall: 3ATP+HCO 3 +NH 4 + +asp
2ADP+AMP+2P i +PP i +fumarate+urea
UREA CYCLE FACTS
Found primarily in liver and lesser extent in kidney
Nitrogen added to the urea cycle via carbamoyl phosphate and aspartate
Carbamoyl phosphate synthetase is allosterically activated by N-acetylglutamate (acetyl CoA + glutamate
N-acetylglutamate)
Arginine stimulates the formation of N-acetylglutamate
HYPERAMMONEMIAS
Acquired = Liver disease leads to portal-systemic shunting Inherited = Urea cycle enzyme defects of CPS I or ornithine transcarbamoylase lead to severe hyperammonemia Fatty liver that can lead to cirrhosis
Alanine,
Serine, Glycine, Threonine
Leucine, Isoleucine, Phenylalanine, Tyrosine GLUCOSE Pyruvate Acetyl CoA Aspartate
Asparagine
Oxaloacetate
Citrate Malate Isocitrate
Phenylalanine Tyrosine Fumarate
Succinate
Succinyl CoA
-Ketoglutarate
Methionine
Isoleucine Valine Glutamate Glutamine
Proline
Figure 6. Fates of carbons from degradation of amino acids
Phenylalanine
Phenylalanine hydroxylase
O 2 H 2 O Tyrosine Tetrahydrobiopterin Dihydrobiopterin NADP + NADPH