LEUCINE METABOLISM

Leucine is one of the essential amino acids, which means it must be obtained through the diet as the body cannot synthesize it. Leucine plays a crucial role in various metabolic processes, particularly in muscle tissue.

Leucine Metabolism
Uptake and Transamination:
Leucine is transported into cells and primarily metabolized in muscle tissue.
The first step involves transamination, where leucine is converted to α-ketoisocaproate (KIC) by the enzyme branched-chain amino acid aminotransferase (BCAT).
Decarboxylation:
KIC undergoes oxidative decarboxylation to isovaleryl-CoA by the branched-chain α-keto acid dehydrogenase complex (BCKD), which is a rate-limiting step in leucine catabolism.
Conversion to Acetyl-CoA and Acetoacetate:
Isovaleryl-CoA is further metabolized to yield acetyl-CoA and acetoacetate.
Acetyl-CoA can enter the citric acid cycle (Krebs cycle) to be used for energy production.
Acetoacetate can be converted into ketone bodies, providing an energy source, particularly during fasting or low-carbohydrate diets.
Regulation:
The metabolism of leucine is tightly regulated by the availability of other branched-chain amino acids (valine and isoleucine) and the activity of BCKD, which is regulated by phosphorylation and dephosphorylation mechanisms.
Insulin and other hormones can influence leucine metabolism by modulating the activity of enzymes involved in the process.
Functions and Importance:
Protein Synthesis:
Leucine is a key regulator of protein synthesis, especially in skeletal muscles, by activating the mTOR (mechanistic target of rapamycin) pathway, which promotes muscle protein synthesis and growth.
Energy Production:
During periods of low carbohydrate intake or intense exercise, leucine can be converted to glucose through gluconeogenesis or used to produce ketone bodies, serving as an important energy source.
Muscle Recovery:
Leucine helps in muscle repair and recovery post-exercise due to its role in stimulating protein synthesis and reducing muscle protein breakdown.
Metabolic Health:
Adequate leucine intake is crucial for maintaining muscle mass and overall metabolic health, particularly in aging populations where muscle mass naturally declines.
Overall, leucine metabolism is essential for energy production, muscle maintenance, and overall metabolic health.

1. LEUCINE METABOLISM UNDERSTANDING THE PATHWAYS AND CLINICAL IMPLICATIONS

2. *Also known as 2-amino-4-methylpentanoyl acid *Discovered by Proust in 1818 *Branched chained, Essential, ketogenic Amino acid *Serves as an alternate source of fuel for the brain *Has roles in blood glu. reg., muscle growth and repair and wound healing INTRODUCTION

3. * It is a small white lustrous plate or crystalline powder * Odourless * It has a melting point of 293C * It is soluble in water, Acetic acid, dilute HCL and alkaline hydroxides and carbonates. * It is slightly bitter * pKa 1( at alpha- carboxyl group)= 2.38(Acidic pKa) * pKa 2( at alpha- ammonium ion)= 9.61(Basic pKa) PROPERTIES

4. STUCTURE *The stereoisomers of leucine are L-leucine and D-leucine. *These are mirror images of each other and are known as enantiomers. * L- leucine is the more abundant form of leucine in mammals, and in humans the only form involved in protein synthesis. *D-leucine is found scarcely in human diet but produced majorly by bacteria and other microorganisms.] *isomeric amino acids include:Leucine,D-isoleucine,L-isoleucine L-tert-leucine, L-Norleucine

5. SOURCES

6. SYNTHESIS *Not synthesized in humans *synthesized in plants and microorganisms *2-ketoisovalerate is an intermediate between valine and leucine synthesis

7. CATABOLISM *Location:Kidney,Muscle,Brain and Adipose tissue(Extra hepatic tissues) *Leucine catabolism doesn’t occur in the liver *CoEnzymes:NAD,FAD,Biotin *Due to the formation of Acetyl CoA and Acetoacetate Leucine is considered ketogenic

8. PRODUCTS/SPECIAL PRODUCTS PRODUCTS FORMED * HMG-CoA: Used in the synthesis of cholesterol and polyisoprenoids. * ACETOACETATE: Ketone body * ACETYL CoA:Fatty acid synthesis and the Citric acid cycle. SPECIAL PRODUCTS FORMED * Leucine peptides * Leucine-rich proteins * HMB (β-Hydroxy β-Methylbutyrate) * Leucine ethyl ester

9. USES It is used for protein synthesis, energy production, and immune function. It Used to Stimulate Muscle Protein Synthesis It Increases Muscle Mass It Improves Athletic Performance It may Promote Weight Loss It may help Stabilize Blood Sugar Prevents Muscle Loss

10. REACTIONS Leucine can be metabolized to propionate Leucine can be converted to isovaleric acid Leucine can also be converted to HMB (beta-hydroxy-beta-methylbutyrate) Leucine can be converted to acetyl-CoA It can also be involved in the formation of alpha-keto acids It can be used to produce other amino acids, such as isoleucine and valine It can activate mTOR

11. DEFICIENCIES Decreased appetite Poor feeding Lethargy Poor growth Weight loss Skin rashes Hair loss Desquamation Leucine deficiency leads to muscle weakness because leucine aids the growth and repair of muscle and bone.

12. IMPORTANCE Leucine also plays a key role in building new muscle tissue Leucine is readily converted to energy during exercise. Leucine also increases the levels of insulin in the blood Leucine stimulates wound healing,and produces growth hormones It is also critical for protein synthesis Prevents Muscle Loss Promotes Muscle Recovery

13. CLINICALS MAPLE SYRUP URINE DISEASE (MSUD): Autosomal recessive disease Branched chain ketoacid dehydrogenase (BCKAD) deficiency Manifestations- Neurological delays Developmental delays Encephalopathy Feeding problems Maple syrup odour of urine High BCAA in urine and blood Treatment- Removal of BCAA from diet

14. CLINICALS ISOVALERIC ACIDEMIA(IVA) Rare, potentially serious inherited condition Inability to fully breakdown leucine Babies with IVA don’t have the enzyme to breakdown Isovaleric acid leading to harmfully high levels of isovaleric acid in the body Symptoms sweaty feet odour,loss of appetite,weight loss, lack of energy, vomiting,irritability,sleepiness,breathing difficulties. Treatment Low protein diet L-carnitine or/and glycine are administered to help clear isovaleric acid

15. CLINICALS 3-METHYLGLUTACONIC ACIDURIA Autosomal recessive disorder Deficiency of 3-methylglutaconyl-CoA Symptoms(occurs at begining of infancy) Developmental delay of motor and mental skills Speech delay involuntary muscle cramping

16. CLINICALS BARTH SYNDROME rare genetic condition that causes severe health issues typically affects boys occurs when a gene mutation affects the body's ability to support cells'energy-producing capabilities leading to issues affecting the heart, muscles, immune system and more Barth syndrome is also known as 3-methylglutaconic aciduria type II SYMPTOMS: enlarged heart, low blood cell count, weakness of muscles,and fatigue Additionally, there can be increased levels ofchemicals like 3-methyglutaconic acid and 2-ethyl hydracrylic acid in the urine or blood

17. CLINICALS BARTH SYNDROME TREATMENT: Symptomatic and complication preventions

18. STRUCTURES Acetyl CoA HMG CoA