This guide provides A Concise Guide To Intra, specifically focusing on enzymes and their crucial role in pharmacology. Enzymes, the biological catalysts, are essential for life, accelerating biochemical reactions within cells. Understanding their function and regulation is paramount in drug development and understanding disease mechanisms.
Enzyme Overview
Enzymes, classified by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC‐IUBMB) based on the reactions they catalyze using a four-number code, play a significant role in biological processes. These biocatalysts fall into six main categories:
- Oxidoreductases (EC 1.‐.‐.‐): Catalyze oxidation-reduction reactions.
- Transferases (EC 2.‐.‐.‐): Transfer functional groups between molecules.
- Hydrolases (EC 3.‐.‐.‐): Facilitate hydrolysis reactions.
- Lyases (EC 4.‐.‐.‐): Break chemical bonds without hydrolysis or oxidation.
- Isomerases (EC 5.‐.‐.‐): Catalyze isomerization reactions.
- Ligases (EC 6.‐.‐.‐): Join molecules together, often coupled with ATP hydrolysis.
While enzymes targeting prokaryotic cells constitute a substantial part of current effective medicines, the total number of enzyme-specific drug targets in the human body is relatively small. Nonetheless, these are of considerable importance.
A simplified illustration of how enzymes are classified based on their function, directly impacting how drugs are designed to interact with them.
Enzyme Inhibition
Most drugs impacting enzymes act as inhibitors. An exception is metformin, which stimulates AMP-activated protein kinase through an imprecise mechanism. Kinetic assays help classify inhibitors as competitive, non-competitive, or un-competitive.
- Competitive inhibitors act at the enzyme’s ligand recognition site.
- Non-competitive inhibitors act at a distinct site, potentially interfering with co-factor or co-enzyme binding.
- Uncompetitive inhibition is rare; lithium ions inhibiting inositol monophosphatase require high substrate concentrations.
- Irreversible inhibitors, including suicide substrates, bind to the ligand recognition site, forming covalent bonds with the enzyme.
While providing mechanistic inhibitor information exceeds the scope of this concise guide to intra, such details are generally available from the cited literature.
Co-factors and Co-enzymes
Enzymes often need additional entities for functionality. Some participate in the catalytic steps, and some promote specific conformational changes.
- Co-factors: Metal ions and heme groups tightly bound to the enzyme.
- Co-enzymes: Small molecules like ATP, NAD, NADP, S-adenosylmethionine, riboflavin (vitamin B1), and thiamine (vitamin B2), which accept or donate functional groups.
The Guide notes the involvement of identified co-factors and co-enzymes.
Enzyme Family Structures and Specific Examples
The following sections provide specific examples of enzyme families and their roles in various biological processes. Each section includes nomenclature, links to resources, inhibitors, and selective inhibitors when available. These families exemplify the breadth and complexity of enzyme involvement in pharmacological targets.
Acetylcholine Turnover
Acetylcholine acts as a neurotransmitter, activating both nicotinic receptors at the neuromuscular junction and muscarinic receptors in smooth muscle. It’s synthesized by choline O‐acetyltransferase (ChAT) and metabolized by acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).
| Enzyme | Abbreviation | HGNC, UniProt | EC Number |
|---|---|---|---|
| Choline O‐acetyltransferase | ChAT | HGNC:1912, P28329 | 2.3.1.6 |
| Acetylcholinesterase | AChE | HGNC:108, P22303 | 3.1.1.7 |
| Butyrylcholinesterase | BChE | HGNC:983, P06276 | 3.1.1.7 |
| Inhibitors | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8807, Ligand:6687, Ligand:6602 | ||
| Selective Inhibitors | http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6599, Ligand:6601 |
Adenosine Turnover
A ubiquitous molecule, adenosine, targets cell-surface G protein-coupled receptors, enzymes, including protein kinases and adenylyl cyclase. Extracellular adenosine is generated by metabolism or export, predominantly through ecto‐5’‐nucleotidase activity and it is inactivated by adenosine deaminase or adenosine kinase.
| Enzyme | Abbreviation | HGNC, UniProt | EC Number |
|---|---|---|---|
| Adenosine deaminase | ADA | HGNC:186, P00813 | 3.5.4.4 |
| Adenosine kinase | ADK | HGNC:257, P55263 | 2.7.1.20 |
| Ecto-5′-nucleotidase | NT5E | HGNC:8021, P21589 | 3.1.3.5 |
| SAHH | SAHH | HGNC:343, P23526 | 3.3.1.1 |
| Selective Inhibitors | Selective adenosine deaminase inhibitors: | Ligand:4805, Ligand:5179 | Ligand:5130, Ligand:5131 |
Amino Acid Hydroxylases
Amino acid hydroxylases (monooxygenases), iron-containing enzymes, use molecular oxygen and tetrahydrobiopterin as co-substrate and co-factor, respectively.
| Enzyme | HGNC, UniProt | EC Number | Endogenous Substrate | Products |
|---|---|---|---|---|
| Phenylalanine hydroxylase | HGNC:8582, P00439 | 1.14.16.1 | Tryptophan | 5‐hydroxytryptophan |
| Tyrosine 3‐monooxygenase | HGNC:11782, P07101 | 1.14.16.2 | 5‐hydroxytryptophan | Serotonin |
| Tryptophan 5‐hydroxylase | HGNC:12008, P17752 | 1.14.16.4 | NA | NA |
| Tryptophan 5‐hydroxylase | HGNC:20692, Q8IWU9 | 1.14.16.4 | NA | NA |
| Selective Inhibitors | Ligand:5095, Ligand:5114, Ligand:5117, Ligand:6956 | Ligand:5095, Ligand:5126, Ligand:5240, Ligand:4613 | Ligand:5095, Ligand:5126, Ligand:5240, Ligand:4613 |
L-Arginine Turnover
L-Arginine, a basic amino acid with a guanidino sidechain, has a crucial role in several metabolic pathways:
- Metabolism to L-ornithine and urea via arginase.
- Precursor for nitric oxide synthase (NOS), producing nitric oxide and L-citrulline.
- Methylation in proteins, forming asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase.
- Hydrolyzed by dimethylarginine dimethylhydrolase to produce L-citrulline and L-ornithine.
Protein Arginine N‐methyltransferases
Protein arginine N‐methyltransferases (PRMT, EC 2.1.1.‐), including histone arginine N‐methyltransferases, use S‐adenosylmethionine as a methyl donor, generating S‐adenosylhomocysteine. They produce both mono‐methylated and di‐methylated products which may be symmetric or asymmetric.
Arginase
Arginase isoforms are manganese-containing enzymes with differential distribution; ARG1 dominates in the liver and erythrocytes, while ARG2 is more common in the kidney.
| Enzyme | HGNC, UniProt | EC Number | Comments |
|---|---|---|---|
| Arginase | NA | 3.5.3.1 | Isoform-selective inhibitors are not available. Intermediate in NOS metabolism of L-arginine acts as a weak inhibitor. |
Arginine:glycine amidinotransferase
| Property | Value |
|---|---|
| Abbreviation | AGAT |
| HGNC, UniProt | HGNC:4175, P50440 |
| EC number | 2.1.4.1 |
Dimethylarginine Dimethylaminohydrolases
Dimethylarginine dimethylaminohydrolases (DDAH) are cytoplasmic enzymes hydrolyzing asymmetric dimethylarginine to form L-citrulline and L-ornithine.
| Enzyme | Abbreviation | HGNC, UniProt | EC Number | Cofactors |
|---|---|---|---|---|
| Dimethylaminohydrolase 1 | DDAH1 | HGNC:2715, O94760 | 3.5.3.18 | Ligand:566 |
| Dimethylaminohydrolase 2 | DDAH2 | HGNC:2716, O95865 | 3.5.3.18 | – |
Nitric Oxide Synthases
Nitric oxide synthases (NOS) synthesize nitric oxide from L-arginine. Functionally, they are distinguished by the cell type expression, intracellular targeting, transcriptional and post-translation mechanisms regulating enzyme activity. Three main isoforms of nitric oxide synthase can be discerned: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS).
| Enzyme | Abbreviation | HGNC, UniProt | EC Number | Endogenous Substrate |
|---|---|---|---|---|
| Endothelial NOS | eNOS | HGNC:7876, P29474 | 1.14.13.39 | L-Arginine |
| Inducible NOS | iNOS | HGNC:7873, P35228 | 1.14.13.39 | L-Arginine |
| Neuronal NOS | nNOS | HGNC:7872, P29475 | 1.14.13.39 | L-Arginine |
Lanosterol Biosynthesis Pathway
The Lanosterol biosynthesis pathway involves enzymes like squalene monooxygenase, squalene synthase, and HMG-CoA reductase. Inhibiting this pathway can affect cholesterol synthesis and, consequently, cellular functions.
| Nomenclature | HGNC, UniProt | EC Number | Comments |
|---|---|---|---|
| Squalene monooxygenase | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:94, http://www.uniprot.org/uniprot/Q9BWD1 | 2.3.1.9 | |
| Squalene synthase | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:5007, http://www.uniprot.org/uniprot/Q01581 | 2.3.3.10 | Mitochondrial (HMGCoA synthase 2) is involved with ketogenesis |
| HMG-CoA reductase | https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7530, http://www.uniprot.org/uniprot/Q03426 | http://www.genome.jp/dbget‐bin/www_bget?ec:1.1.1.34 | HMGCoA reductase is associated with intracellular membranes |
Chromatin Modifying Enzymes
Chromatin modifying enzymes control cell identity and regulate differentiation, proliferation, and genome integrity. These enzymes are divided into:
- Writers: Such as histone methyltransferases and acetyltransferases.
- Readers: Contain methyl-lysine recognition motifs.
- Erasers: Include histone demethylases and deacetylases.
Eicosanoid Turnover
Eicosanoids, derived from arachidonic acid, are metabolized through:
- Cyclooxygenase (COX): Forms prostaglandins and thromboxanes.
- Lipoxygenases (LOXs): Generate hydroperoxyeicosatetraenoic acids (HPETEs).
- Cytochrome P450-like epoxygenases.
Sphingosine 1-phosphate Turnover
S1P, a bioactive lipid, acts on S1P-specific G protein-coupled receptors and has intracellular targets. It’s formed by sphingosine kinase and dephosphorylated by sphingosine 1‐phosphate phosphatase, or cleaved by sphingosine 1‐phosphate lyase.
Glycerophospholipid Turnover
Glycerophospholipids are basic barrier components of eukaryotic cell membranes. Key enzymes include:
- Phosphoinositide-specific phospholipase C (PLC): Hydrolyzes phosphatidylinositol 4,5-bisphosphate.
- Phospholipase A2 (PLA2): Cleaves fatty acids from phospholipids.
- Phosphatidylcholine‐specific phospholipase D (PLD): Forms phosphatidic acid.
These enzymes participate in various signaling pathways.
Peptidases and Proteinases
These enzymes hydrolyze peptide bonds and are divided into exopeptidases (aminopeptidases, carboxypeptidases) and endopeptidases (serine, cysteine, aspartate, metallo, threonine endopeptidases).
Conclusion
This concise guide to intra focused on the structure, function, and pharmacological significance of enzymes provides a foundational understanding for researchers and students in pharmacology, biochemistry, and drug development. Enzymes, though often a small subset of drug targets, are paramount in influencing physiology and disease.
