Amino Acid Metabiolism

Date and Time: Monday, November 4th at 11:30
Location: LAS A
Material covered: From Lecture 8 (Carbohydrates) to Lecture 14 (Nitrogen Metabolism)
Office Hours: Today at Founders 206, from 2:00 – 3:00
Online Office Hours: Sunday, November 3rd, from 9:00 to 10:00

Location: Takes place in the cytoplasm.
Key Point: Need a mechanism to transport mitochondrial Acetyl-CoA to the cytoplasm.

Dietary Interactions:
- High Carbohydrate: Influences glucose levels.
- Low Blood Glucose: Affects fatty acid metabolism.
Key intermediates:
- Fatty acyl-CoA
- Malonyl-CoA: Substrate for fatty acid synthesis.
Hormonal Regulation:
- Insulin and Glucagon interplay in metabolism.
Pathway Components:
- Fatty acyl-CoA
- Carnitine: Assists in the transfer of fatty acids.

Chylomicrons:
- Synthesized in the intestinal mucosa.
- Transport triacylglycerols to tissues.
VLDL (Very Low-Density Lipoproteins):
- Synthesized in the liver.
- Deliver triacylglycerols to adipose tissue.
LDL (Low-Density Lipoproteins):
- Major cholesterol carrier: often referred to as the "bad" cholesterol.
HDL (High-Density Lipoproteins):
- Highest protein content; responsible for picking up cholesterol from tissues and transporting it to the liver (considered "good").

Biological Requirement: Nitrogen must be reduced to NH3/NH4+ for use in biological systems.
Sources of Nitrogen:
- Reduction of oxides of nitrogen (NO3, NO2) and atmospheric N2.
Amino Acid Metabolism:
- Essential in nitrogen cycle, specifically for amino acids.

N2 Gas:
- Comprises 80% of the atmosphere but is stable and difficult to reduce.
- Requires high pressure and temperature for chemical reduction.
Biological Reduction:
- Accomplished by nitrogen-fixing bacteria (e.g., Rhizobium) through a symbiotic relationship with legume plants.

Nitrogenase Complex:
- Composed of dinitrogenase reductase (Fe-S) and dinitrogenase (molybdenum-iron).
- Capable of converting N2 to NH3 using electrons from donor sources (like NADH) and ATP.
Reaction Summary:
- N2 + 10H+ + 8 e- + 16 ATP  2NH4 + 16 ADP + 16 Pi + H2
Anaerobic Conditions:
- Nitrogenase is inactivated by O2; needs anaerobic conditions facilitated by leghemoglobin in Rhizobium.

Source of NH4+: Required for amino acid synthesis. High levels of NH4+ are toxic and assimilated through glutamate amination.
Glutamine Regulation:
- Glutamine synthase is highly regulated due to its integration in multiple metabolic pathways.

Role in Glutamate Formation:
- Two methods to produce glutamate: via glutamate dehydrogenase and glutamine synthase.
- Significance in transporting NH4+ from tissues to the liver.
Amides and Amino Groups: Many amino acids derive amino groups from glutamine through glutamine amidotransferase.

Transamination Process:
- Transfers amino groups from glutamate to α-keto acids, producing α-ketoglutarate and amino acids.
Role of Cofactors: All aminotransferases utilize PLP (Pyridoxal phosphate) as a cofactor, which is derived from Vitamin B6.

Carbon Skeleton Sources: Amino acids acquire carbon skeletons from glycolysis, citric acid cycle, or pentose phosphate pathway intermediates. The amino group typically comes from glutamate.

Reasons to Catabolize Amino Acids:a) Cannot be stored, excess must be broken down.b) Normal protein turnover.c) Starvation/diabetes.
Initial Step: Typically starts with deamination (removal of amino group).

General Catabolic Pathway: Carbon skeletons from amino acid breakdown enter the citric acid cycle, while NH4+ is excreted through the urea cycle.

Central Importance of Specific Amino Acids:
- Glutamate, glutamine, alanine, aspartate (can be converted into citric acid cycle intermediates).
Connections to Other Metabolic Processes:
- Conversion to α-ketoglutarate, oxaloacetate, and pyruvate respectively.

Glucose-Alanine Cycle:
- Transfers nitrogen from muscle tissues back to the liver by converting alanine to pyruvate and glucose.
Glutamate in Muscle Metabolism:
- Central metabolite for transferring nitrogen.

Phenylketonuria (PKU):
- Caused by deficiency in phenylalanine hydroxylase; leads to high levels of phenylalanine and atypical byproducts, potentially resulting in mental retardation if untreated. Dietary management includes low phenylalanine and high tyrosine.

Excretion Methods in Animals:
- Primarily through urea synthesis; uric acid is excreted in birds and terrestrial reptiles.

Location: Urea cycle occurs in the liver.
Nitrogen Sources in Urea: Nitrogens lost during urea formation typically come from aspartate and carbamoyl phosphate, often delivered to the liver as glutamate or glutamine.
ATP Requirement: Requires energy expenditure (2 ATP to ADP + 1 ATP to AMP).

Clinical Symptoms:
- Hyperammonemia, nausea after ingestion of protein, gradual mental retardation.
Causes: Genetic deficiencies of enzymes in the urea cycle cause reduced enzyme activity.
Treatment: Low-protein diets supplemented with α-keto acids to mitigate excess NH4+.

Physiological Importance:
- Specialized pathways convert amino acids into bioactive compounds such as histamine (from histidine) and melatonin (from tryptophan).
- Tyrosine and phenylalanine proficiently synthesize neurotransmitters like epinephrine and dopamine.

Modes of Transport from Muscle to Liver:
- Options include:a) NH4b) Alaninec) Glutamated) Glutamine.