Amino Acids #2

Isoleucine, leucine, valine

Muscle

High serum levels of BCAA indicate pre-diabetes

Break down of body protein (~400 g), dietary protein (~100 g), and de novo synthesis of nonessential AAs (varies)

• 1. Urea cycle
• 2. Synthesis of body protein
• 3. Glucogenic/ketogenic AAs --> glucose, CO2 + ATP, ketone bodies, FAs, steroids. (6)
• 4. Synthesis of porphyrins, creatinine, neurotransmitters, purines, pyrimidines (5)

• 1. AAs are immediately degraded
• 2. GNG or directly into TCA cycle

• 1. Separate a-amino group from C skeleton
• 2. Shunt each into specialized metabolic pathway

NH4+ from liver & other organs --> liver to be excreted as urea.

C skeleton --> pyruvate, acetyl CoA or other TCA intermediates. 

Vitamin B6 (pyridoxal phosphate) and all capable of reversible rxns 

Cofactor for transaminases - amino group is transferred via pyridoxal phosphate. B6+NH3 = pyridoxamine phosphate. 

AST = aspartate aminotransferase.

Transfers amino group from glutamate to oxaloacetate forming aspartate. 

Yes, it is reversible. 

ALT or AST is released into blood during normal cell turnover (cell dies and releases contents into blood). However, elevated levels indicate damage to cells high in these enzymes.

ALT is more specific for liver disease.

AST is more sensitive due to higher levels in liver. 

Liver disease, myocardial infarction, muscle disorder, extensive cell necrosis, severe viral hepatitis, toxic injury and prolonged circulatory collapse.

a-ketoglutarate

Glutamate + a-keto acid

1. Help maintain adequate levels of non-essential AAs required for protein synthesis.

2. Funneling amino groups from catabolized AAs to glutamate & aspartate for eventual excretion as urea.

Positive N balance --> catabolism to excrete excess amino acids --> ALT will go towards creating glutamate. 

Negative N balance --> catabolism of body protein to create energy due to low ATP and GTP levels.

Either way, there is transaminase activity!

High levels of circulating amino acids may promote insulin resistance possibly via disruption of insulin signaling in skeletal muscle.

Obese non-diabetic Chinese/Asian-Indian insulin resistant men and obese siblings of pairs of obesity discordant monozygotic twins.

Oxidative deamination in liver/kidney via glutamate DH. 

• 1. Glutamate is transferred to  liver for oxidative deamination via glutaminase, then in liver its broken back down into glutamate and NH3. 
• 2. In liver/kidney glutamate -- glutamate DH --> a-ketoglutarate + free NH3. 
• 3. A-ketoglutarate is recycled.

Activated by ADP and GDP allosterically (low energy)

Inhibited by ATP and GTP

Also depends on concentrations of rxns and products: relative concentrations of glutamate:a-ketoglutarate, ammonia, and oxidized to reduced coenzymes.

Goes strongly towards production of a-ketoglutarate and free NH3 (catabolism)

Starvation --> low ATP:ADP and low GTP:GDP, so need high AA degradation to get energy production from C skeletons, thus increased synthesis of a-ketoglutarate for TCA cycle or for GNG. 

Also get amino acid degradation and ammonia production.  In liver, rxn proceeds in direction of AA degradation and formation of ammonia to get rid of excess protein. BUT CAN ALSO GET AA SYNTHESIS FROM CORRESPONDING A-KETO ACIDS. 

Increased protein --> increased glutamate

In most tissues: glutamate + NH3 + ATP -- glutamine synthetase --> glutamine (nontoxic transport form of 2 ammonias) --> liver.

• Muscle (glucose alanine cycle):
• Transamination of pyruvate to form alanine. Alanine is transported to liver via blood and is converted to pyruvate and glutamate --> GNG.

Main purpose: major route for NH3 disposal.

ATP - 3

2 Ns: NH3 (oxidative deamination) and from aspartate combine with CO2. 

BUN = blood urea nitrogen

Will be high with faulty urea synthesis (faulty waste disposal).

Measures nitrogen balance

Activated by high protein diet, high protein meal containing arginine, N-acetylglutamate, and starvation. 

1. Long-term: Activated by high protein diet (increased use of protein for energy/catabolism --> increased urea) also activated by starvation (use of body protein as energy) upregulates autophagy and expression of urea cycle enzymes. 

2. Short-term: N-acetylglutamate - allosteric activator of carbamoyl phosphate synthetase 1 (CPS1)

N acetylglutamate is formed from acetylCoA + glutamate and its synthesis is increased by arginine (in protein rich meal).

high levels of alanine apparently

During negative N balance, even though protein degradation does occur during positive N balance. 

Caused by defect in oniline enzyme. 

Vomiting, cerebral edema, coma, irritability, excessive sleepiness 

• 1. Altered metabolism of important compounds (pyruvate, lactate, glycogen, glucose)
• 2. Changes in NMDA and GABA receptors
• 3. Free radical production & induction of membrane permeability transition phenomenon leading to mitochondrial dysfunction.

Melanin synthesis from tyrosine.

Tyrosinase

Lack of pigment

Urea synthesis. 

CPS-1

Lethargy, convulsions, early death

Branched chain AA degradation.

Branched chain a-keto acid dehydrogenase

Mental disease, retardation, early death

Conversion of Phe --> Tyr

Phenylalanine hydroxylase

Mental retardation

Easiest to treat, can be treated via diet. (low protein diet + tyrosine supplements) Pregnant women must continue treatment to prevent birth defects.