Met-enkephalin, also known as metenkefalin ( INN), sometimes referred to as opioid growth factor (OGF), is a

naturally occurring A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical ...

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

opioid peptide Opioid peptides or opiate peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these p ...

that has

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

effects of a relatively short duration. It is one of the two forms of

enkephalin An enkephalin is a pentapeptide involved in regulating nociception (pain sensation) in the body. The enkephalins are termed endogenous ligands, as they are internally derived (and therefore endogenous) and bind as ligands to the body's opioid ...

, the other being

leu-enkephalin Leu-enkephalin is an endogenous opioid peptide neurotransmitter with the amino acid sequence Tyr-Gly-Gly-Phe-Leu that is found naturally in the brains of many animals, including humans. It is one of the two forms of enkephalin; the other is met ...

. The enkephalins are considered to be the primary endogenous ligands of the

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi alpha subunit, Gi/G0 and has enkephalins as it ...

, due to their high potency and selectivity for the site over the other endogenous opioids.

History

Met-enkephalin was discovered and characterized by John Hughes, Hans Kosterlitz, ''et al''. in 1975 after a search for endogenous ligands of the opioid receptors.

Chemistry

Met-enkephalin is a pentapeptide with the

amino acid sequence Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthe ...

tyr-gly-gly-phe-met. The

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...

residue at position 1 is thought to be analogous to the 3-

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

group A group is a number of persons or things that are located, gathered, or classed together. Groups of people * Cultural group, a group whose members share the same cultural identity * Ethnic group, a group whose members share the same ethnic iden ...

morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

Biochemistry

Distribution

Met-enkephalin is found mainly in the

adrenal medulla The adrenal medulla () is the inner part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of chromaffin cells that secrete catecho ...

and throughout the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

(CNS), including in the

striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...

, olfactory tubercle,

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

septum In biology, a septum (Latin language, Latin for ''something that encloses''; septa) is a wall, dividing a Body cavity, cavity or structure into smaller ones. A cavity or structure divided in this way may be referred to as septate. Examples Hum ...

thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...

, and

periaqueductal gray The periaqueductal gray (PAG), also known as the central gray, is a brain region that plays a critical role in autonomic function, motivated behavior and behavioural responses to threatening stimuli. PAG is also the primary control center for ...

, as well as the dorsal horn of the

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...

. It is also present in the periphery, notably in some primary afferent fibers that

innervate A nerve is an enclosed, cable-like bundle of nerve fibers (called axons). Nerves have historically been considered the basic units of the peripheral nervous system. A nerve provides a common pathway for the electrochemical nerve impulses called ...

the pelvic viscera.

Biosynthesis

Met-enkephalin is synthesized from proenkephalin via proteolytic

cleavage Cleavage may refer to: Science * Cleavage (crystal), the way in which a crystal or mineral tends to split * Cleavage (embryo), the division of cells in an early embryo * Cleavage (geology), foliation of rock perpendicular to stress, a result of ...

in two

metabolic Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the ...

steps. Proenkephalin A is first reduced by either one of two

trypsin Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the dig ...

-like endopeptidase

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s, prohormone convertase 1 (PC1) or prohormone convertase 2 (PC2); then, the resulting intermediates are further reduced by the enzyme carboxypeptidase E (CPE; previously known as enkephalin convertase (EC)). Proenkephalin A contains four sequences of met-enkephalin (at the following positions: 100–104; 107–111; 136–140; 210–214), and as a result, its cleavage generates four copies of met-enkephalin peptides at once. In addition, anabolism of proenkephalin A results in the production of one copy each of two

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

-extended met-enkephalin derivatives, the heptapeptide met-enkephalin-arg-phe (261–267), and the octapeptide met-enkephalin-arg-gly-leu (186–193), though whether they affect the opioid receptors in a similar manner as met-enkephalin is not entirely clear.

Clearance

Met- and leu-enkephalin are metabolized by a variety of different enzymes, including aminopeptidase N (APN),

neutral endopeptidase Neprilysin (; also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10) and common acute lymphoblastic leukemia antigen (CALLA)) is an enzyme that in humans is encoded by the ''MME'' ge ...

(NEP), dipeptidyl peptidase 3 (DPP3), carboxypeptidase A6 (CPA6), and

angiotensin-converting enzyme Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasocon ...

(ACE). These enzymes are sometimes referred to as enkephalinases.

Biological activity

Met-enkephalin is a potent

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the

, and to a lesser extent the

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...

, with little to no effect on the

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four re ...

. It is through these receptors that met-enkephalin produces its opioid effects, such as

analgesia Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...

and

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

-like effects. It is also the endogenous

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

of the opioid growth factor receptor (OGFR; formerly known as the ζ-opioid receptor), which plays a role in the regulation of tissue growth and regeneration; hence why met-enkephalin is sometimes called OGF instead.

Pharmacokinetics

Met-enkephalin has low

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

, is rapidly metabolized, and has a very short

half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...

(minutes). These properties are considered undesirable in pharmaceuticals as large doses would need to be administered multiple times an hour to maintain a therapeutically relevant effect, making it unlikely that met-enkephalin will ever be used as a medicine. -Ala2Met-enkephalinamide (DALA), is a synthetic enkephalin analog which is not susceptible to degradation by brain enzymes and at low doses (5 to 10 micrograms) caused profound, long-lasting, morphine-like analgesia when microinjected into a rat’s brain.

References

{{DEFAULTSORT:Met-enkephalin Opioid peptides Delta-opioid receptor agonists Pentapeptides