sign in sign up
<<
Home , Arginine (data page), Carbamoyl phosphate, Catabolism, Deamination, Histidine (data page), Oxidative deamination

BI/CH 422/622 OUTLINE: OUTLINE: Degradation () Amino- Degradation Inside of cells Cycle – dealing with the Protein turnover Ubiquitin Feeding the Activation-E1 - Cycle Conjugation-E2 Free Ligation-E3 Proteosome Amino-Acid Degradation Ammonia Overall energetics free Dealing with the transamination-mechanism to know Seven Families Urea Cycle – dealing with the nitrogen 1. ADENQ 5 Steps 2. RPH Carbamoyl- synthetase oxidase transcarbamylase one-carbon Arginino-succinate synthetase THF Arginino-succinase SAM 3. GSC Energetics PLP uses Urea Bi-cycle 4. MT – one carbon metabolism 5. FY – oxidases

Amino Acid Catabolism: Urea Cycle The Urea Bi-Cycle Two issues:

1) What to do with the fumarate?

2) What are the sources of the free ammonia? a-ketoglutarate a-

Aspartate transaminase

a-keto acid Glutamate

1 Amino Acid Catabolism: Urea Cycle The Glucose-Alanine Cycle • Vigorously working muscles operate nearly anaerobically and rely on for .

a-Keto • Glycolysis yields pyruvate. – If not eliminated (converted to acetyl- CoA), will build up. • If amino acids have become a fuel source, this lactate is converted back to pyruvate, then converted to alanine for transport into the . Excess Glutamate is Metabolized in the Mitochondria of

Amino Acid Catabolism: Urea Cycle Excess glutamine is processed in the intestines, kidneys, and liver.

(deaminating) (N,Q,H,S,T,G,M,W)

OAA

à Asp

Glutamine Synthetase

This costs another ATP, bringing it closer to 5

(N,Q,H,S,T,G,M,W) 29 N

2 Amino Acid Catabolism: Urea Cycle Excess glutamine is processed in the intestines, kidneys, and liver.

(deaminating) (N,Q,H,S,T,G,M,W)

OAA

à Asp

Glutamine Synthetase

This costs another ATP, bringing it closer to 5

(N,Q,H,S,T,G,M,W)

Amino Acid Catabolism: Urea Cycle Regulation of the Glutamate Urea Cycle Urea Cycle Dehydrogenase

+

NADP+ H

NADPH

Allosteric inhibitors: GTP, ATP, Palmitoyl-CoA • The pool of Glu is a critical junction between and catabolism Allosteric Activators: ADP, , ,

• The represents a key link Schiff between catabolic and anabolic pathways; formation when biosynthesis is needed, its off and Glu provides for amino-acid biosynthesis. When energy is needed, the ammonia is • GluDH has a high K value (>1 mM) for ammonia, so pulled off to provide for the urea cycle and m it mostly functions to provide the initial material for the oxidation of carbon skeletons. urea cycle; ammonia, using NAD+, which is high when • Can use either NAD+ in the catabolic energy charge is low. direction (oxidative ), or • Ammonia is processed into urea for . Carbon NADPH in the biosynthetic direction. skeletons are oxidized for ATP.

3 Amino Acid Catabolism: Urea Cycle Regulation of the Urea Cycle

•Urea production is controlled by synthetase. •N-acetylglutamate is an allosteric activator. •Carbamoyl phosphate synthetase I is activated by N-acetylglutamate. •Formed by N-acetylglutamate synthase –when glutamate and acetyl-CoA N-acetyl- concentrations are high glutamate

–Km values are 1 and 0.7 mM, respectively

–activated by (Ki value of 10 µM!) •Expression of urea cycle increases when needed. –high-protein diet –starvation, when protein is being broken down for energy

Amino Acid Catabolism: Urea Cycle Excretory Forms of Nitrogen: Fates of Nitrogen in Organisms • Plants conserve almost all the nitrogen. • Many aquatic vertebrates release ammonia to their environment. –passive diffusion from epithelial cells –active transport via gills • Many terrestrial vertebrates and excrete nitrogen in the form of urea. –Urea is far less toxic that ammonia. –Urea has very high . –Requires lots of • Some animals such as and excrete nitrogen as . –Uric acid is rather insoluble. –Excretion as paste allows the animals to conserve water. • Humans and great apes excrete both Ure-otelic urea (from amino acids) and uric acid (from purines). Uric-otelic

4 Amino Acid Catabolism: Urea Cycle Energetics of Urea Cycle & Amino acid degradation Example: 2 GluDH NADP+ à NADPH 2.5 MDHcyto Pyr NAD+ à NADH 2.5 Ala 5 Per Pyruvate in Krebs Cycle: 4 NAD+ à 4 NADH 10 FAD à FADH2 1.5 GTP 1 aKG 12.5 x 2 = 25 Ala 25 + 5 = 30 – 4 to 5 (Urea Cycle) Pyr Glu ~13 ATP per Ala

Amino Acid Degradation: the carbon “skeletons” A. Concepts 1. Convergent 2. ketogenic/glucogenic The SEVEN (7) Families 3. Reactions seen before B. Transaminase (A,D,E) / Deaminase (N,Q) Family C. Related to biosynthesis (R,P,H; G,S,C; T,M) 1.Glu Family a. Introduce oxidases/oxygenases b. Introduce one-carbon metabolism (1C) 2.Pyruvate Family a. PLP reactions 3. a-ketobutyric Family a. 1-C metabolism D. Dedicated (F,Y; K,W; V,I,L) 1. Aromatic Family a. oxidases/oxygenases 2. a-ketoadipic Family 3. Branched-chain Family 29 N

5 Amino Acid Degradation

• Intermediates of the central • Some amino acids result in more than one intermediate. • Ketogenic amino acids can be converted to bodies. Seven to Acetyl-CoA Leu, Ile, Thr, Lys, Phe, Tyr, Trp • Glucogenic amino acids can be converted to glucose.

Six to pyruvate1 Ala, Cys, Gly, Ser, Thr, Trp Five to a-ketoglutarate2 Arg, Glu, Gln, His, Pro Four to succinyl-CoA Ile, Met, Thr, Val Two to fumarate3 Phe, Tyr Two to oxaloacetate4 Asp, Asn

1Pyruvate family 2Glu family 3Aromatic family 4Trans-/de-aminase family

Amino Acid Degradation A,D,E

Simple Transamination

PLP

PLP

+ + PLP

6 Amino Acid Degradation N,Q

Simple Deamination

PLP

+ + PLP

Amino Acid Degradation A,D,E,N,Q

• Intermediates of the central metabolic pathway • Some amino acids result in more than one intermediate. • Ketogenic amino acids can be converted to ketone bodies. Seven to Acetyl-CoA Leu, Ile, Thr, Lys, Phe, Tyr, Trp • Glucogenic amino acids can be converted to glucose.

Six to pyruvate1 Ala, Cys, Gly, Ser, Thr, Trp Five to a-ketoglutarate2 Arg, Glu, Gln, His, Pro Four to succinyl-CoA Ile, Met, Thr, Val Two to fumarate3 Phe, Tyr Two to oxaloacetate4 Asp, Asn

1Pyruvate family 2Glu family 3Aromatic family 4Trans-/de-aminase family

7 Amino Acid Degradation R,P,H

Glu Family Arginine degradation is part of the urea cycle.

PLP

Proline, arginine, and are all converted to glutamate.

Histidine-ammonia lyase uricanase Imidazolone- propionase Glu-formiminotransferase

Histidine Urocanate Imidazolone- Formimino propionate glutamate

Two new metabolic concepts used: 1) Oxidase 2) One-carbon metabolism

N 5N 10-Methenyl N 5-Formimino THF THF

Amino Acid Degradation R,P,H

Glu Family Arginine degradation is part of the urea cycle.

PLP

Proline, arginine, and histidine are all converted to glutamate.

Histidine-ammonia lyase uricanase Imidazolone- propionase Glu-formiminotransferase

Histidine Urocanate Imidazolone- Formimino propionate glutamate

Two new metabolic concepts used: 1) Oxidase 2) One-carbon metabolism

N 5N 10-Methenyl N 5-Formimino THF THF

8 Amino Acid Degradation: One Carbon

H H H • Tetrahydrofolate is formed H from folate.

dihydro – an essential – Folate is reduced to dihydrofolate, then to tetrahydrofolate (THF) • It is used in a wide variety of metabolic reactions. • THF can transfer 1-carbon in different oxidation states.

– CH3, CH2OH, and CHO • Carbon generally comes from . • Forms are interconverted on THF before use.

9