NAME: | Jobs Jacobs Zuma Biolae | COURSE | INTERMEDIARY METABOLISM | COURSE CODE | BCH 803 | | |

Conditions that favor the use of protein as source of energy and how it is achieved.
The fraction of metabolic energy obtained from amino acids, whether they are derived from dietary protein or from tissue protein, varies greatly with the type of organism and with metabolic conditions.
In animals, amino acids undergo oxidative degradation in different metabolic circumstances:
1. During the normal synthesis and degradation of cellular proteins (protein turnover): some amino acids that are released from protein breakdown and are not needed for new protein synthesis undergo oxidative degradation
2. When a diet is rich in protein and the ingested amino acids exceed the body’s needs for protein: synthesis, the surplus is catabolised; amino acids cannot be stored.
3. During starvation or in uncontrolled diabetes mellitus: when carbohydrates are either unavailable or not properly utilized, cellular proteins are used as fuel.
4. Cachexia: wasting of body tissues as seen in cancer and other chronic illnesses
Under all these metabolic conditions, amino acids lose their amino groups to form alpha-keto acids, the carbon skeletons of amino acids. The alpha-keto acids undergo oxidation to CO2 and H2O or, often more importantly, provide three- and four-carbon units that can be converted by gluconeogenesis into glucose, the fuel for brain, skeletal muscle, and other tissues.

One important feature distinguishing amino acid degradation from other catabolic processes is that every amino acid contains an amino group, and the pathways for amino acid degradation therefore include a key step in which the alpha-amino group is separated from the carbon skeleton and shunted into the pathways of amino group metabolism.

An overview of amino acid catabolism in mammals.
The key functional amino acids necessary for amino acid metabolism are:
*Glutamine
*Glutamate
*Alanine
*Aspartate

Glutamate and glutamine play especially critical roles in nitrogen metabolism, acting as a kind of general collection point for amino groups. In the cytosol of hepatocytes, amino groups from most amino acids are transferred to alpha-ketoglutarate to form glutamate, which enters mitochondria and gives up its amino group to form NH4+.
Excess ammonia generated in most other tissues is converted to the amide nitrogen of glutamine, which passes to the liver, then into liver mitochondria. Glutamine or glutamate or both are present in higher concentrations than other amino acids in most tissues. In skeletal muscle, excess amino groups are generally transferred to pyruvate to form alanine, another important molecule in the transport of amino groups to the liver.

STARVATION
Starvation is a condition in which there is depletion or unavailability of vital nutrients for optimal health. In normal physiologic state, carbohydrates serve primarily as energy source especially since they are readily oxidized to yield high-energy compounds such as adenine triphosphate, ATP and other high-energy phosphate molecules.
Secondary to carbohydrates as energy source is the oxidation of lipids through lipolysis to provide substrate which are invariably fed into the Kreb’s Cycle to yield energy. Proteins serve as last resort alternatives in being oxidized having first undergone deamination to give rise to short-chain carbon skeletons which are used as fuel or used in the synthesis of glucose (gluconeogenesis) during starvation.

Metabolic Adaptation
This involves the process of taking on alternative sources of fuel to sustain physiological processes. In starvation and other stress-inducing conditions listed above, alternative pathways are harnessed to yield glucose especially for organs that greatly depend on it like the brain.
The activation of these pathways is a function of the interplay between hormones, enzymes and substrates. Thus, the following metabolic priorities are considered:
*Gluconeogenesis
*Transamination and Deamination

Gluconeogenesis, derivation from tissue proteins
In starvation glucose concentration is markedly decreased and invariably results in a drop of the plasma concentration of insulin which is secreted by the β-islets cells of the pancreas. Since insulin influences the presentation of glucose transporters on the surface of most tissues, these transporters (GLUT 4) are resorped into intracellular vesicles.
By reason of the reciprocal correlation between insulin and glucagon, glucagon is secreted to counter the hypoglycemic state of plasma by inhibiting glycogen synthetase while activating glycogen phosphorylase in the liver. The resulting glucose 6 phosphate is hydrolysed by glucose 6 phosphatase, releasing glucose into the blood stream.
Glucagon also inactivates pyruvate kinase and activates phosphoenol pyruvate carboxykinase in the liver to facilitate gluconeogenesis.
Muscle glycogen cannot contribute directly to plasma glucose since it lacks glucose-6-phosphatase. To therefore supply glucose to the blood, it makes use of an indirect energy-saving process employing the inhibitory action of accumulated pyruvate in the muscle consequent to the inhibition of pyruvate dehydrogenase by a buildup of acetyl CoA due to fatty acid oxidation. This pyruvate is transaminated to Alanine at the expense of amino acids from muscle tissue. The Alanine and keto-acids resulting from this is exported from the muscle and taken up by the liver, where the Alanine is transaminated to yield pyruvate. Thus, this cycle continues at the expense of muscle tissue protein. This is a similar process found in other tissues during starvation.

METABOLISM IN DIABETES MELLITUS TYPE 1
Insulin deficiency is a protein catabolic state. Insulin enhances short-side-chain amino acid intracellular uptake, stimulates transcription and translation of RNA, increases the gene expression of albumin and other proteins and inhibits liver protein breakdown enzymes. In insulin-dependent diabetes mellitus (IDDM) patients most of the whole-body protein turnover studies have shown that insulin deficiency increases protein breakdown and increases amino acid oxidation and that these effects are reversed by insulin treatment. Recent studies have demonstrated that a substantial increase in leucine transamination during insulin deprivation contributes to leucine catabolism in IDDM patients. Protein synthesis in the insulin-deprived state is also increased although to a lesser extent than protein breakdown, and this increased whole-body protein synthesis is reduced with an insulin infusion; thus the effects of insulin are largely mediated through its effects on protein breakdown. The metabolic derangements in diabetes frequently involve disturbances in substrates and hormones other than insulin

Conditions that favor the use of Ketone bodies as energy source.
In adipose tissue the decrease in insulin and increase in glucagon results in inhibition of lipogenesis, inactivation of lipoprotein lipase and activation of intracellular hormone-sensitive lipase. The overall result of this is the increased amount of glycerol (a substrate for gluconeogenesis) and free fatty acids used by heart, liver and skeletal muscles as their preferred metabolic fuel, and at the same time sparring glucose.
Although muscles preferentially take up and metabolise free fatty acids in the fasting state, this cannot meet all its energy requirements by β oxidation. Contrastingly, the liver has a better capacity for β oxidation than it requires to meet its own energy needs, and as fasting is prolonged, it forms more acetyl CoA than can be oxidized. This acetyl CoA is used to synthesize the ketone bodies which are used as major fuels for skeletal and heart muscles, and still also meet some of the brain’s energy needs.
In prolonged starvation, glucose may represent less than 10% of whole body energy-yielding metabolism.
As fasting is prolongedthe plasma concentration of ketone bodies increase markedly as shown in the graph below using the relative changes of metabolic parameters during the onset of starvation:

This also reveals the influence of hormones such as insulin and glucagon relative to the ketone body and free fatty acid concentration in plasma