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Figure_1._The_structure_of_leucine_(image_adapted_from_PubChem)Leucine, classified as an essential amino acid, is a cornerstone of protein synthesis and metabolic regulation in the human body. The discovery of leucine occurred in 1819 when French chemist Étienne Ossian Henry isolated leucine from cheese protein, marking the first documented instance of its extraction. Henry's groundbreaking work laid the foundation for further investigations into the structure and functions of amino acids. Leucine's molecular structure is composed by a central carbon atom and four different chemical groups: an amino group (-NH2), a carboxyl group (-COOH), a hydrogen atom (-H), and a branched methyl group (-CH2-CH(CH3)2)

Leucine Biosynthesis

Figure_2._The_synthesis_pathway_of_leucine_in_plants [1]Leucine biosynthesis is a complex process involving several enzymatic reactions that occur primarily in plants, bacteria, and some fungi. Unlike animals, which cannot synthesize leucine and other essential amino acids de novo, organisms capable of leucine biosynthesis rely on specific metabolic pathways to produce this amino acid. Here's a step-by-step overview of the key processes and molecules involved in leucine biosynthesis [1]:

1.Acetolactate Synthase (ALS) Reaction

The first step in leucine biosynthesis involves the condensation of two molecules of pyruvate to form 2-acetolactate. This reaction is catalyzed by the enzyme acetolactate synthase (ALS), also known as acetohydroxy acid synthase (AHAS). ALS is a key regulatory enzyme in the biosynthesis of branched-chain amino acids (leucine, isoleucine, and valine).

2.Acetohydroxy Acid Isomeroreductase (AHAIR) Reaction

The 2-acetolactate produced in the first step is then converted into 2,3-dihydroxyisovalerate by the enzyme acetohydroxy acid isomeroreductase (AHAIR). This reaction involves the reduction of the ketone group and isomerization of the molecule.

3.Dihydroxyacid Dehydratase (DHAD) Reaction

In the next step, 2,3-dihydroxyisovalerate undergoes dehydration catalyzed by dihydroxyacid dehydratase (DHAD), yielding alpha-ketoisovalerate.

4.Transamination and Amino Group Transfer

Alpha-ketoisovalerate is then transaminated, wherein an amino group from glutamate is transferred to the alpha-keto acid, forming α-ketoisocaproate (α-KIC), the precursor to leucine. This transamination reaction is catalyzed by branched-chain amino acid aminotransferase (BCAT), which is also involved in the metabolism of leucine.

5.Decarboxylation and Final Steps

The final steps involve the decarboxylation of α-ketoisocaproate to yield leucine. The exact mechanisms and enzymes involved in this decarboxylation step may vary among organisms.

Leucine Metabolism

Leucine metabolism involves a series of intricate biochemical processes within the human body, encompassing both catabolic and anabolic pathways. The primary route of leucine metabolism occurs in various tissues, including skeletal muscle, liver, and adipose tissue. Here's a detailed overview of the key steps and molecules involved in leucine metabolism [2,3]:

1.Transport into Cells

Leucine is transported into cells via specific amino acid transporters, such as the L-type amino acid transporter 1 (LAT1), which facilitates its entry into tissues.

2.Branch Chain Amino Acid (BCAA) Transamination

Once inside the cell, leucine undergoes transamination, a process catalyzed by the enzyme branched-chain amino acid aminotransferase (BCAT). This reaction transfers the amino group from leucine to alpha-ketoglutarate, forming alpha-ketoisocaproate (α-KIC) and glutamate.

3.Ketoacid Dehydrogenase Complex

Alpha-ketoisocaproate (α-KIC) is further metabolized by the branched-chain alpha-ketoacid dehydrogenase complex (BCKDC), which catalyzes a series of reactions to generate acetyl-CoA and succinyl-CoA. This complex is regulated by the phosphorylation status of its components, with phosphorylation inhibiting its activity.

4.Entry into the Citric Acid Cycle

Acetyl-CoA generated from leucine metabolism enters the citric acid cycle (also known as the tricarboxylic acid cycle or Krebs cycle), where it undergoes oxidation to produce energy in the form of ATP.

5.Anabolic Pathways

In addition to its role in energy production, leucine also serves as a precursor for the synthesis of other molecules. For instance, alpha-ketoisocaproate (α-KIC) can be converted into HMG-CoA, a precursor for cholesterol synthesis, or used for fatty acid synthesis.

Figure_3._Metabolic_pathway_of_leucine [3]

Functions of Leucine in Human Health and Diseases

Leucine in Muscle Wasting and Sarcopenia

Leucine acts as a potent stimulator of protein synthesis, particularly in skeletal muscle, by activating the mammalian target of rapamycin (mTOR) signaling pathway [4]. Elevated leucine levels in the cell trigger mTOR complex 1 (mTORC1) activation, leading to the phosphorylation of downstream targets like S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1). Consequently, this cascade facilitates increased mRNA translation, promoting muscle growth and repair [5-7]. By stimulating protein synthesis and inhibiting protein degradation pathways, particularly through mTOR activation, leucine shows promise in preserving muscle mass and function amidst aging and disease-related muscle loss. Leucine supplementation has been investigated as a potential therapeutic approach for muscle wasting conditions such as sarcopenia and cachexia [8,9]. 

Leucine in Type 2 Diabetes

Leucine plays a key role in regulating insulin secretion from pancreatic beta cells, contributing to glucose homeostasis [10,11]. It stimulates insulin release by depolarizing the beta cell membrane potential through the activation of ATP-sensitive potassium (KATP) channels, leading to calcium influx. This mechanism supports insulin secretion in response to elevated blood glucose levels. Implicated in the pathogenesis and management of type 2 diabetes, leucine supplementation has been studied for its potential to enhance insulin secretion and improve insulin sensitivity in peripheral tissues, thereby promoting better glycemic control [12,13]. Additionally, leucine's activation of the mTOR signaling pathway plays a crucial role in regulating glucose metabolism and insulin action [14].

Leucine in Neurological disorders

Leucine serves as a precursor for neurotransmitters like glutamate and gamma-aminobutyric acid (GABA) in the brain, essential for neuronal signaling, mood regulation, and cognitive function. Leucine plays a role in neurological disorders such as epilepsy and neurodegenerative diseases. Studies have shown that leucine supplementation may have anticonvulsant effects and improve seizure control in epilepsy patients [15,16]. Additionally, leucine metabolism contributes to neurotransmitter synthesis in the brain, influencing neuronal excitability and synaptic transmission. Alterations in leucine metabolism have also been implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's disease [17-19].

Leucine in Cancers

Leucine exhibits multifaceted roles in cancer progression, impacting various aspects of tumor biology [20-22]. It stimulates tumor cell proliferation and survival by activating the mammalian target of rapamycin (mTOR) signaling pathway, promoting protein synthesis, cell cycle progression, and cell survival pathways. Additionally, leucine contributes to metabolic reprogramming in cancer cells, enhancing aerobic glycolysis and lactate production to support tumor growth. Lastly, leucine may contribute to cancer metastasis by promoting epithelial-mesenchymal transition (EMT), enhancing the invasive and metastatic potential of cancer cells. 

Leucine in Lipid Metabolism

Leucine exerts multifaceted effects on lipid metabolism by regulating various aspects of lipid synthesis, storage, and utilization [23-26]. It stimulates lipogenesis by upregulating the expression of key lipogenic genes such as fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC) through activation of the mammalian target of rapamycin (mTOR) signaling pathway, which in turn activates sterol regulatory element-binding protein 1 (SREBP-1), a master regulator of lipogenic gene expression. Additionally, leucine attenuates lipolysis in adipocytes by inhibiting hormone-sensitive lipase (HSL), thereby promoting lipid storage and adipocyte hypertrophy. Moreover, leucine enhances lipid oxidation by stimulating the expression and activity of enzymes involved in fatty acid oxidation, such as carnitine palmitoyltransferase I (CPT1) and acyl-CoA dehydrogenase (ACAD), facilitating the breakdown of fatty acids for energy production. Furthermore, leucine increases the expression of fatty acid transport proteins (FATPs) and fatty acid translocase (FAT/CD36) in peripheral tissues, promoting the uptake of fatty acids from circulation and enhancing lipid uptake and storage.


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