Chemical classification of hormones

Goals / what you need to know

• To distinguish the chemical classes of hormones

• To recognize the chemical structure of hormones
• To identify hormones of related structure and their cross-talks
Hormone classification based on chemical nature

• Proteins
• Hormones of anterior pituitary except ACTH, insulin, parathyroid hormone
• Peptides
• ACTH, calcitonin, glucagon, vasopressin, oxytocin, hormones of hypothalamus
(releasing factors and statins)- somatostatins, TRH, GnRH
• Amino acid derivatives
• Dopamine, Catecholamine (epinephrine and norepinephrine), thyroxin
• Steroids – derivatives of cholesterol
• Hormones of the adrenal cortex, sex hormones
• Derivatives of polyunsaturated fatty acid – arachidonic acid and Vits
• Prostaglandins
Characteristics
• Secretion
• Peptide and protein hormones by exocytosis
• Steroids (lipophilic) hormones continuously penetrate the membrane
• Transport
• Protein and peptide in free state
• Steroids and thyroid gland hormones bound with alpha globulins or albumins
• Catecholamines in free state or bound with albumins, sulphates or glucuronic acid
• Receptors
• On the surface of membrane – peptide and protein hormones, prostaglandins
• Inside the cells – cytoplasm, nucleus – steroid and thyroid hormones
Protein Hormones
Insulin
• Protein hormone by beta cells of the pancreatic islets
• The main anabolic hormone of the body
• Human insulin protein is
• composed of 51 amino acids
• A dimer of an A-chain and a B-chain
• Linked by disulfide bonds
• Among species of animals
• Structure varies slightly
• differs some what in effectiveness
Cont
Cont
• Preproinsulin
• First synthesized insulin
• a single polypeptide in beta cells
• contains a 24-residue signal peptide
• Directs the nascent polypeptide chain to the rough endoplasmic reticulum (RER)
• Cleaved as the polypeptide is translocated into lumen to the RER forming proinsulin
• Proinsulin
• In the RER
• the proinsulin folds into the correct conformation
• 3 disulfide bonds are formed
• About 5-10 min its assembly
• Proinsulin is transported to the trans-Golgi network (TGN)
• immature granules are formed
• Transport to the TGN may take about 30 min
Cont
• Mature insulin
• Proinsulin undergoes maturation
• Active insulin formation
• through the action of cellular endopeptidases
• prohormone convertases (PC1 and PC2)
• The endopeptidases cleave at 2 positions
• Release a fragment called the C-peptide and leaving 2 peptide chains the B-
and A- chains linked by 2 disulfide bonds
• The cleavage sites are each located after a pair of basic residues
• Lysine 64 and arginine 65 and
• Arginine 31 and 32
Cont
• C-peptide
• C-peptide is the central portion of proinsulin
• primary sequence of proinsulin goes in the order “B-C-A”
• The resulting mature insulin is packaged inside mature granules
waiting for metabolic signals
• Such as leucine, arginine, glucose and mannose and
• Vagal nerve stimulation
• Exocytosed from the cell into the circulation
Cont
• The preproinsulin precursor of insulin
• encoded by the INS gene
• The amino acid sequence of insulin is strongly conserved
• Strong homology seen in the insulin sequence of diverse species
• Been conserved across much of animal evolutionary history
• Proinsulin
• however differs much more among species
• Also a hormone but secondary one
Cont
• Porcine insulin
• Especially close to the human version
• Only in one AA
• Widely used to treat type 1 diabetes before human insulin produced by
recombinant DNA technologies
• Bovine insulin
• differes from human in only three amino acids
• Some species of fish
• similar enough to be clinically effective in humans
Cont
• Hexamer vs monomer
• Insulin produced and stored in the body as a hexamer
• A unit of six insulin molecule
• inactive form
• long term stability
• highly reactive insulin protected, yet readily available
• The active form is the monomer
• diffusion rate is inversely related to particle size-Much faster reacting
• The hexamer-monomer conversion
• the central aspects of insulin formulation for injection
Cont
• Hexamer is far more stable than the monomer – desirable for
practical reasons
• Monomer
• A fast-reacting drug
• means insulin injections do not have to precede mealtimes by hours
• Which in turn gives people with diabetes more flexibility in their daily
schedules
Cont
Cont
Rapid-acting
Long acting
Cont
• Insulin, insulin-like growth factors (IGF) 1 and IGF-II share structural
similarities
• Most apparent when precursor forms compared
• High degree of specificity seen with the glycoprotein hormones
• There is moderate cross-talk among the members of the insulin/IGF family
• Eg high conc of an IGF-II precursor produced by certain tumors (eg sarcomas) can cause
hypoglycemia
• Partly because of binding to insulin and IGF-I receptors
• High conc of insulin also bind to the IGF-I receptor
• Perhaps accounting for some of the clinical manifestation seen in severe
insulin resistance
IGF
FSH, LH, TSH and hCG as a family
• Hormone families
• Reflecting their structural similarities
• Many hormones and receptors can be grouped
• They evolve together
• Generates diverse actions
• Recognizing these relationships allows
• Extrapolation of information from one hormone or receptor to other family member
• FSH, LH, TSH and hCG
• Protein dimers
• contains 2 glycopeptidic subunits
• labeled alpha and beta subunits
• non-covalently associated (i.e., without any disulfide bridge linking them)
Cont
Cont
• The alpha subunits of the glycoproteins LH, FSH, TSH, and hCG
• identical
• 92 amino acids in human but 96 amino acids in almost all other vertebrate
species
• The beta subunits vary
• Both subunits are required for biological activity
Cont
• The cloning of the b-subunit genes from multiple species suggests
• This family arose from a common ancestral gene
• Probably by gene duplication and subsequent divergence to evolve new
biologic function
• As the hormone families enlarge and diverge
• Their receptors must co-evolve
• Its new biologic functions are to be derived
• Have evolved for each of the glycoprotein hormones
Cont
• However there is minimal overlap of hormone binding
TSH
• binds with high specificity to the TSH receptor
• but interacts weakly with the LH or the FSH receptor
• there can be subtle physiologic consequences of hormone cross-
reactivity
• Very high levels of hCG during pregnancy
• stimulate the TSH receptor and increased thyroid hormone levels
Cont
• Follicular stimulating hormone
• beta subunit of 111 amino acids (FSH β)
• confers its specific biologic action, and
• responsible for interaction with the follicle-stimulating hormone receptor
• The sugar portion of the hormone is
• covalently bonded to asparagine and
• composed of
• N-acetylgalactosamine,
• mannose,
• N-acetylglucosamine,
• galactose and
• sialic acid
Cont
• Lutenizing hormone
• beta subunit of 120 amino acids (LH β)
• confers its specific biologic action
• hCG
• beta subunit contains an additional 24 amino acids, and
• differ in the composition of their sugar moieties
• The different composition of these oligosaccharides affects
• bioactivity and
• speed of degradation.
• The biologic half-life of
• LH is 20 minutes,
• FSH (3–4 hours) and
• hCG (24 hours)
Cont
• Thyroid stimulating hormone
• The β (beta) subunit (TSHB) is unique to TSH
• determines its receptor specificity
• The β chain has a 118-amino acid sequence
• The α subunit
• the effector region
• responsible for stimulation of adenylate cyclase (involved the generation of
cAMP)
• The α chain has a 92-amino acid sequence
Cont
• HCG
• Human chorionic gonadotropin is glycoprotein composed of 237
amino acids
• The β-subunit of hCG gonadotropin (beta-hCG)
• contains 145 amino acids,
• encoded by six highly homologous genes
Cont
Growth hormone
• Protein hormone that stimulates growth
• 191-amino acids
• single-chain polypeptide
• Synthesized, stored and secreted by somatotropic cells
• The structure includes four helices necessary for functional
interaction with the GH receptor.
• In structure GH is evolutionarily homologous to prolactin
Cont
Prolactin
• Is a protein –enabling females to produce milk
• a 198 amino acid protein
• Encoded by PRL gene
• The structure similar to that of growth hormone
• a 40% sequence homology to GH
• arose from a common ancestral gene
• duplicated about 400 million years ago
• diverged approximately 50 million years ago yielded the two modern hormones
• folded due to three disulfide bonds
• The non-glycosylated is dominant form
Cont
• The three different sizes of prolactin are:
• Little prolactin—the predominant form
• It has a molecular weight of appxoximately 22-kDa.
• It is a single-chain polypeptide of 198 amino acids and is apparently the result of
removal of some amino acids.
• Big prolactin—approximately 48 kDa.
• It may be the product of interaction of several prolactin molecules.
• It appears to have little, if any, biological activity.
• Big big prolactin—approximately 150 kDa.
• It appears to have a low biological activity.
• The levels vary
Cont
Parathyroid hormone
• When the calcium in blood goes too low
• Increased PTH causes
• body to put more calcium into the blood Increased
• bones to release their calcium into the blood
• hPTH-(1-34) crystallizes as a slightly bent, long helical dimer
Adiponectin
• Adiponectin is secreted from
• adipose tissue and
• the placenta in pregnancy
• Adiponectin is a 244-amino-acid-long polypeptide
• There are four distinct regions of adiponectin
• The first is a short signal sequence that targets the hormone for secretion
outside the cell;
• next is a short region that varies between species;
• the third is a 65-amino acid region with similarity to collagenous proteins
• the last is a globular domain
Cont
• glucose flux
• decreased gluconeogenesis
• increased glucose uptake
• lipid catabolism
• β-oxidation
• triglyceride clearance
• protection from endothelial dysfunction (important facet of
atherosclerotic formation)
• insulin sensitivity
• weight loss
• control of energy metabolism
Peptide hormones
Glucagon
• Peptide hormone
• By the alpha cells of the pancreas
• It works to raise the concentration of
• glucose
• fat in the blood stream
• Main catabolic hormone of the body
• Elevates the concentration of glucose in the blood by promoting
• gluconeogenesis
• glycogenolysis
• Glucagon also decreases fatty acid synthesis in adipose tissue and the liver
• Promoting lipolysis in these tissue
Cont
• Glucagon is a 29-amino acid polypeptide
• Its primary structure in humans is:
• NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-
Trp-Leu-Met-Asn-Thr-COOH.
• Generated from the cleavage of
• proglucagon proprotein
• By convertase 2 in pancreatic islet α cells
• In intestinal L cells
• proglucagon is cleaved to the alternate products
• glicentin,
• GLP-1 (an incretin),
• IP-1 and intervening peptide 2
• GLP-2
• Promotes intestinal growth
Cont
Cont
• Intestinal L Cells
• Have Proteases in neuroendocrine cells
• process proglucagon differently than do α cells
• produce four peptide fragments:
• Glicentin contains the amino-acid sequence of glucagon but does not bind to
glucagon receptors
• Both GLP-1 and GLP-2 are glucagon-like
• they cross-react with glucagon,
• but GLP-1 and GLP-2 have very weak biological activity as glucagon analogs
• However, GLP-1—released by the gut into the circulation in response to carbohydrate or protein
ingestion—is one of the most potent incretins, stimulating insulin secretion
• GLP-2 is not an incretin, and its biological actions are not known
Adrenocorticotropic hormone ACTH, Corticotropin

• ACTH consists of 39 amino acids

• produced in a process that also generates several other hormones
• proopiomelanocortin (POMC, "Big Mama")
• A large precursor protein
• synthesized and proteolytically chopped into several fragments
• the first 13 of which (counting from the N-terminus)
• cleaved to form α-melanocyte-stimulating hormone (α-MSH) and CLIP
• After a short period of time
• responsible for excessively tanned skin in Addison's disease
• CLIP peptide with unknown activity in humans - Corticotropin like intermediate
peptide CLIP
Cont
Cont
• Lipotropin:
• Originally described as having weak lipolytic effects,
• its major importance is as the precursor to beta-endorphin
• Beta-endorphin and Met-enkephalin:
• Opioid peptides with pain-alleviation and euphoric effects
• Melanocyte-stimulating hormone (MSH):
• Known to control melanin pigmentation in the skin of most vertebrates
Oxytocin / Vasopressin
• by the posterior lobe of the pituitary gland
• Oxytocin
• causes contraction of the uterus during child birth
• Vasopressin
• controls the reabsorption of water in the kidneys
• The structure of oxytocin is very similar to that of vasopressin
• Both are nonapeptides
• with a single disulfide bridge
• differing only by two substitutions in the amino acid sequence
Cont
Cont
• ADH and oxytocin differences
• Amino acid positions 3 and 8 make all the difference
• Position 3 is in the ring,
• in both hormones forces a hydrophobic group (Ile or Phe)
• Each type of receptor must have a hydrophobic pocket in this region
• That for ADH is larger than that of oxytocin.
• The big difference is at position 8.
• ADH has a large group
• positively charged at physiological pH,
• oxytocin has a medium size lipophilic group
• This difference determines the specific recognition of the hormones by their
receptors
Angiotensin
• Peptide hormone
• causes vasoconstriction and an increase in blood pressure
• a part of the renin–angiotensin system
• which is a major target for drugs that raises blood pressure
• derived from the precursor molecule angiotensinogen, a serum
globulin produced in the liver
• Another hormone angiotensin II an octapeptide is a potent
vasoconstrictor
Calcitonin
• A 32-amino acid linear polypeptide
• the parafollicular cells (also known as C-cells) of the thyroid gland,
• It acts to reduce blood calcium (Ca2+)
• opposing the effects of PTH
Amino acid derivative hormones
Amine hormones
• Water soluble amino compounds
• Eg – adrenaline – (epinephrine) and thyroid hormones
• Derived from amino acids
• So these hormones are called amino acid derivatives
• Adrenaline is needed to prepare for emergency in several ways
• Increases the heart beat rate,
• the heart output and
• the blood pressure preparing the cardiovascular system for emergency action
Cont
Epinephrine and Norepinephrine
• Norepinephrine is a catecholamine and a phenethylamine
• Its structure differs from epinephrine
• epinephrine has a methyl group attached to its nitrogen,
• methyl group is replaced by a hydrogen atom in norepinephrine
• The prefix nor- is derived as an abbreviation of the word "normal“
• used to indicate a demethylated compound
Dopamine
• Consists of a catechol structure
• a benzene ring with two hydroxyl side groups
• one amine group attached via an ethyl chain
• Dopamine is the simplest catecholamine
• Also includes the neurotransmitters norepinephrine and epinephrine
• benzene ring + amine attachment makes it a substituted phenethylamine
• a family that includes numerous psychoactive drugs
• dopamine is an organic base
• protonated in acidic environments - relatively stable
• In basic environments not protonated - more highly reactive
• chemical or pharmaceutical use as dopamine hydrochloride protonated form
• dopamine is combined with hydrochloric acid
Thyroid hormone
• Require
• Thyroglobulin
• Iodine
• Amino acid thyrosine
• Thyroxine (T4) contains four iodine atoms.
• Deiodination leads to production of the potent hormone
triiodothyronine (T3) or the inactive hormone reverse T3
Cont
Steroid hormones
Steroid hormones
• Steroids are the compounds whose structure is based on a four-ring
network
• Consisting of three cyclohexane rings and one cyclopentane ring
• Steroid alcohols are called sterols
• Sterols are fat-soluble
• Cholesterol is the most common sterol
• It is a part of all cell-membranes and is the starting point for the
synthesis of all other steroids
• Important amongst steroid hormones are the sex hormones
Cont
Fatty acid derivatives
Eicosanoids
• Eicosanoids
• fatty acid derivatives
• with a variety of extremely potent hormonelike actions on various tissues
• Unlike hormones, they are not transported between tissues in the blood,
• act on the tissue produced
• involved in reproductive function; in the inflammation, fever, and pain associated with injury or disease
• Eicosanoids are all derived from the 20-carbon polyunsaturated fatty acid arachidonic acid,
20:4(Δ5,8,11,14)
• three classes :
• prostaglandins,
• thromboxanes, and
• leukotrienes.
• Various eicosanoids are produced in different cell types by different synthetic pathways, and
have different target cells and biological actions
Cont
Cont
• Nomenclature
• PG- prostaglandins
• Letter A, B, E and F
• Originally E for ether because extracted by ether
• F phospate buffer – Swedish fosfat
• A and B by treatment with acid and base
• Subscripts
• No of double bonds