PROTEIN METABOLISM OVERVIEW

OVERALL METABOLISM OF PROTEINS All proteins in the body are continuously degraded (metabolized) and newly synthesized Free AA from food, tissue proteins and non-essential AA from synthesis make AA pool AA pool is used for: 1. New body proteins 2.Specialized products (amines, porphyrines, Nucleic Acid bases ...) 3. Catabolic proceses (energy gain)

In healthy, well fed individuals, the input to the amino acid pool is balanced by the output, that is, the amount of amino acids contained in the pool is constant. The amino acid pool is said to be in a steady state. The amino acid pool is a grand mixture of amino acids available in the cell derived from dietary sources or the degradation of protein. Since proteins and amino acids are not stored in the body, there is a constant turnover of protein.

AA pool Definition: AA POOL It includes the free AAs distributed throughout the body ~ 80 % in muscles ~ 10 % in liver ~ 5 % in kidney ~ 5 % in blood In contrast to the amount of protein in the body (about 12 Kg in 70 Kg man), the AA. pool is small (only 100 gm. 50% of these AAs are in the form of glutamate & glutamine (Why?). ) AA pool is not reserve !! There is no specific protein reserve in human body in contrast to saccharides (liver glycogen) and lipids (adip. tissue) !!

SOURCES & FATE OF THE AA. POOL Non essential a.a.s synthesized in the body Diatery proteins Tissue proteins a.a.s Amino acid pool Anabolism Catabolism(Deamination) Synthesis of Fate of deamination products Proteins Other nitrogenous compounds α- keto acid Ammonia ►Aminosugars ►Nitrogenous bases of phospholipids ►Purines & pyrimidines ►Neurotransmitters ►Niacin ►Creatine ►Heme Krebs cycle ►Tissue proteins ►Plasma proteins ►Enzymes ►Some hormones ►Milk Ketone bodies Synthetic pathway Catabolic pathway glucose CO2+H2O +ENERGY Non essential a.a.synthesis Excreted in urine glutamine Urea

Some protein is constantly being synthesized while other protein is being degraded. For example, liver and plasma proteins have a half-life of 180 days or more, while enzymes and hormones may be recycled in a matter of minutes or hours.

Nitrogen Balance nitrogen balance is achieved by a healthy person when the dietary intake is balanced by the excretion of urea wastes. If nitrogen excretion is greater than the nitrogen content of the diet, the person is said to be in negative nitrogen balance. This is usually interpreted as an indication of tissue destruction. If the nitrogen excretion is less than the content of the diet, a positive nitrogen balance indicates the formation of protein.

Protein turnover Human proteins have very different lifetimes. Total body protein is about 12 kg, but about 25% of this is collagen, which is metabolically inert. A typical muscle protein might survive for three weeks, but many liver enzymes turn over in a couple of days. Some regulatory enzymes have half-lives measured in hours or minutes. The majority of the amino acids released during protein degradation are promptly re-incorporated into fresh proteins.

Protein turnover The recommended minimal protein intake required to achieve nitrogen balance in healthy adults is about 50g per day, although in developed countries many people may eat double this amount. This compares with an average daily protein turnover of about 250g per day. Most of the ingested protein is ultimately oxidized to provide energy, and the surplus nitrogen is excreted, a little as ammonia but mostly as urea.

Protein degradation: Two major enzyme systems responsible for degrading damaged or unneeded proteins

The ATP-dependent ubiquitin-proteasome system of the cytosol Soluble intracellular proteins are tagged for destruction by attaching ubiquitin, a low molecular weight protein marker. They are then degraded in proteasomes to short peptides

The ATP-independent degradative enzyme system of the lysosomes The ATP-independent degradative enzyme system of the lysosomes. Proteasomes degrade mainly endogenous proteins, that is, proteins that were synthesized within the cell. Lysosomal enzymes (acid hydrolases, degrade primarily extracellular proteins, such as plasma proteins that are taken into the cell by endocytosis, and cell-surface membrane proteins that are used in receptor-mediated endocytosis.

DEFECTS OF UBIQUITINATION Angelman Syndrome Von Hippel Lindau Syndrome

Angelman Syndrome Angelman syndrome is a genetic disorder that causes developmental disabilities and neurological problems, such as difficulty speaking, balancing and walking, and, in some cases, seizures. Frequent smiles and outbursts of laughter are common for people with Angelman syndrome, and many have happy, excitable personalities.

People with Angelman syndrome tend to live a normal life span People with Angelman syndrome tend to live a normal life span. But they may become less excitable and develop sleep problems that may improve with age. Angelman syndrome usually isn't detected until parents begin to notice developmental delays when a baby is about 6 to 12 months old. Seizures often begin when a child is between 2 and 3 years old. Treatment focuses on managing medical and developmental issues.

Von Hippel Lindau Syndrome

Von Hippel Lindau Syndrome

Transport of AA into cells Amino acid uptake from the gut lumen into enterocytes is driven by the sodium gradient. There is a relatively high sodium concentration in the gut and a low concentration in the enterocytes, as a result of the sodium pump in the basolateral membrane.

The concentration of free amino acids in the extracellular fluids is significantly lower than that within the cells of the body. This concentration gradient is maintained because active transport systems, driven by the hydrolysis of ATP, are required for movement of amino acids from the extracellular space into cells.

At least seven different transport systems are known that have overlapping specificities for different amino acids The small intestine and the proximal tubule of the kidney have common transport systems for amino acid uptake; therefore, a defect in any one of these systems results in an inability to absorb particular amino acids into the gut and into the kidney tubules

For example, one system is responsible for the uptake of cystine and the dibasic amino acids, ornithine, arginine, and lysine (represented as “COAL”). In the inherited disorder cystinuria, this carrier system is defective, and all four amino acids appear in the urine

CYSTINURIA occurs at a frequency of 1 in 7,000 individuals, making it one of the most common inherited diseases, and the most common genetic error of amino acid transport. The disease expresses itself clinically by the precipitation of cystine to form kidney stones (calculi), which can block the urinary tract. Oral hydration is an important part of treatment for this disorder.

HARTNUP DISEASE Is also referred to as Hartnup disorder. It’s a hereditary metabolic disorder. It makes it difficult for body to absorb certain amino acids from intestine and reabsorb them from kidneys. In most people, body absorbs specific amino acids into intestines and then reabsorbs them in kidneys. If you have Hartnup disease, you can’t properly absorb certain amino acids from small intestine. Also they can’t be reabsorbed from kidneys. As a result, an excessive amount of amino acids exits from body through urination.

As a result of excessive loss of amino acids from body through urination. This leaves the body with an insufficient amount of these amino acids. Without enough tryptophan, body can’t produce enough niacin. A niacin deficiency can cause to develop Pellagra like symptoms which include dermatitis( a sun-sensitive rash) diarrhea and dementia.