Enzymes Involved in Glycolysis, Fatty Acid and Amino Acid Biosynthesis: Active Site Mechanisms and Inhibition

Marco Brito-Arias

• Publisher: Bentham Science Publishers
• Year: 2020
• Print ISBN: 9789811460883
• eBook ISBN: 9789811460906
• Topic: Biological Sciences
• Subtopic: Biochemistry
• Index: Biological Sciences

Multidisciplinary research involving crystallography, kinetic studies, molecular docking, genetics and other techniques in biochemistry has yielded a wealth of knowledge about the reaction mechanisms in cellular processes. This knowledge has allowed researchers to understand, in a better way, the normal functioning of the cell process, which is used as a reference point for learning about and preventing or correcting pathologies that cause diseases.
This enzymology reference is a thorough compendium about reaction mechanisms occurring between the major enzymes related to the biosynthetic pathways of 3 important types of biological compounds – 6-carbon carbohydrates, fatty acids and amino acids – and their substrates, cofactors and residues. Readers will gain an understanding of the interaction between substrates or ligands with specific amino acid residues in biosynthetic enzymes. This understanding builds a foundation for learning about the biochemistry of different inhibitors used in the treatment of several diseases such as cancer, infectious diseases, and metabolic syndrome alterations such as diabetes and obesity.
Enzymes covered in the book include aldolases, isomerases, kinases, mutases, synthases, dehydrogenases, reductases, transferases, hydrolases, lyases among others, all of which are wide spread in biochemical transformations.
This reference, with its insights on common biochemical enzymes serves as a handy guide for students, researchers and professionals involved academia or industry related to pharmaceutical development, healthcare, food chemistry and other disciplines.

Aminoacid Biosynthesis

Marco Brito-Arias^*

Unidad Profesional Interdisciplinaria de Biotecnología, Instituto Politécnico Nacional (UPIBI-IPN), Mexico

Amino acids are biomolecules composed of an amino group and carboxylic acid as common features and different R substituents attached to a chiral carbon with L-configuration for the biologically active enantiomer in humans except for glycine devoid of chirality (Fig. 129). Biosynthetically, the amino acids are derived from glycolysis, Krebs cycle or the pentose phosphate pathway.

Fig. (129))
Tetrahedral projection of amino acids.

Based on additional functionalities present in the amino acids, they can be classified in aliphatic, aromatic, polar (hydroxyl and thiol groups), cationic, anionic, and heterocyclic groups (Fig. 130).

1. GLYCINE BIOSYNTHESIS

Glycine is the simplest amino acid having hydrogen as R substituent, and therefore not presenting chirality. It is an amino acid with important implications in brain excitatory and inhibitory activities, and in the synthesis of other essential molecules such as muscle supplement creatine, antioxidant glutathione, and as an abundant component in the structural protein collagen. This amino acid is synthesized from amino acids serine, threonine or nutrient choline, and its detailed biosynthesis is described in the following sections (Fig. 131).

Fig. (130))
Classification and structure of amino acids.

Fig. (131))
General scheme of glycine biosynthetic precursors.

Glycine biosynthesis from serine as starting material is carried out by the catalysis of the enzyme serine hydroxyl methyl transferase (SHMT) with participation of tetrahydropteroylglutamate (H₄PteGlu), which is converted to 5,10-methylene tetrahydropteroylglutamate (5,10-MH₄PteGlu), and pyridoxal phosphate (B6) as cofactors (Fig. 132).

Fig. (132))
General scheme of glycine biosynthesis from serine in the presence of tetrahydrofolate and pyridoxal phosphate cofactors.

An early mechanism suggested that the conversion of L-serine to glycine involved formaldehyde formation, however further studies with mutants determined that instead of formaldehyde formation, a direct nucleophile displacement of the serine hydroxyl by N⁵ of tetrahydropteroylglutamate (H₄PteGlu) occurs, giving place to glycine and 5,10-methylene-H₄PteGlu. The reaction mechanism satisfying this transformation proposes a retroaldol from N⁵ of THF making an attack on C3 serine resulting in C3-C2 cleavage of serine (Fig. 133) [141].

Fig. (133))
Proposed reaction mechanism for glycine formation involving PLP and H₄PteGlu.

1.1. Serine Hydroxyl Methyl Transferase (SHMT)

The crystal structure of SHMT from Methanocaidococcus jannaschii in the apo form (mjSHMT without cofactor PLP) and holo form (mjSHMT with PLP) was determined, showing the catalytic domain in purple, the C-terminal in green, the N-terminal α-helix in yellow, and cofactor PLP in red spheres (Fig. 134) [142, 143].

Fig. (134))
The ribbon structure of G monomer SHMT from Methanocaidococcus jannaschii G monomer showing the catalytic domain in purple, the C-terminal in green, and PLP as spheres in red (PDB: 4BHD).

Native serine hydroxymethyltransferase from Bacillus stearothermophilus complexed with serine has been described, allowing the identification of the residues and the cofactors participating. The SHMT stereoview shows the aldimide and THF interacting with serine and glycine (Fi...

Table of contents

• Welcome
• Table of Content
• Title
• BENTHAM SCIENCE PUBLISHERS LTD.
• PREFACE
• ACKNOWLEDGEMENTS
• Glycolysis
• Citric Acid Cycle (Krebs)
• Fatty Acid Biosynthesis
• Aminoacid Biosynthesis
• References