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Vitamins


Definition

Vitamins are a group og organic nutrients, required in small quantities for a variety of biochemical functions and maintenance of normal metabolic functions, that arent synthesized in body and therefore must be supplied in diet.


》vit D, K2 and B3 are synthesized in body


Henderson s Equation

pH=pKa+log( base/acid)

Hormone having Cell Receptors?

Epinephrine

Insulin Receptor is Linked to?

Tyrosine Kinase

Ratio of Conjugate Base to Acid is 1 if?

pH=pKa

Domain

Fundamental functional structure

GAGs


Repeating disaccharide units

Suger involved in Determining Blood Groups

Frustose

Epimer

Glucose differs in 2 and 4

Mucoproteins

Have more than 4% hexoses amines

Difference between Water and Fat Soluble Vitamins

Fat Soluble


hydrophobic. Require normal fat absorption for efficient absorption, transported from intestine inthe form of chylomicrons and circulate in blood in combination with specific binding proteins (like other lipids)


》Functions diverse functions


> vit A: vision and cell differentiation


> VitD: calcium and phosphate metabolism


> vitE: antioxidants


> vitK: role in blood clotting


》Deficiency: dietary inadequacy or conditions affecting digestion and absorption of lipids e.g steatorrhoea, biliary tract diseases


》Toxicity: from excessive intake e.g hypervitaminosis A and D



Water Soluble


soulbe in water


》Functions; as coenzymes


> TPP:Coenzyme form of B1


> FMN, FAD: Coenzyme form of B2


> NAD+, NADP+: coenzyme form of B3


》Deficiency: dietary inadequacy


》Toxicity: not common as excessive amounts are secreted

Vitamin A


Forms

Retinol: primary alcohol, contains B-ionone ring with unsaturated side chain, combines with long chain FA to form retinyl esters in animal tissue


Retinal: aldehyde derived from oxidation of retinol. Retinal and retinol are interconvertable


Retinoic Acid: derived from oxidation of retinal, cant be converted to retinol or retinal in blood cause it cant be reduced


B-Carotene: can be oxidatively cleaved to give 2 molecules of retinal but conversion is not very efficient


Retinoids: comprise retinol, retinal, retinoic acid


> preformed vit A


> Found only in foods of animal origin


Carotenoids: comorise carotenes and related compounds


> precursors of vit A(pro vitA)


> foundin plants

Vitamers

One of several chemically related compounds posessing a given vitamin activity

Receptors


Definition

Cell associated recognition molecules

CARM

Receptors


Properties

1.Protein in nature


2.have Recognition and binding Domains


3.have high affinity for their Ligands


4.binding of ligands to receptors is highly specific, saturable and reversible.


5.discriminate precisley


6.not static components of cell, but their numbers inc or dec, in response to various stimuli(up and down regulation), and their properties very with change in physiologic conditions

Receptors


Up Regulation

In presence of deficiency of chemical messengers, theres an inc in number of active receptors

Receptors


Down Regulation

In presence of excess of chemical messengers, theres a dec innumber of active receptors.


>down regulation of cell surface receptors isbrought about by internalization (endocytosis)


>down regulation of intracellular receptors is brought about byreducing the receptor mRNA which dec the concentration of receptor molecules

Receptors


Functions

Two basic functions:


1. To bind hormones


2. To couple hormone binding to signal transduction

Receptors


Classification

1.Intracellular Receptors:


> located in cytoplasm or in nucleus and include those for steroid hormones, vit D derivatives, retinoic acid, thyroid hormone


> these ligands are highly hydrophobic or lipophilic and readily permeate through the plasma membrane of target cells andbind to these receptors


2.Cell Surface Receptors:


> located in plasma membrane


> act as recognition sites for a vast majority of signalling molecules which are too big or too hydrophilic to crossthe target cell plasma membrane and hence bind to the cell surface receptors(integral membrane proteins)

G Proteins


General characteristics

Guanine nucleotide-binding proteins


constitute a subgroup of family of proteins which can bind and hydrolyze GTP called GTPases


》Signalling Mechanism is exchange of GDP for GTP as a switch to allow or inhibit biochemical reactions


》Small G Proteins or GTPases e.g Ras aremonomeric and not membrane associated(not coupled to membrane proteins, occur in cytosol), but bind GDP nad GTP


> Active Raslroteins stimulate a family of protein kinases that trigger MAP kinase cascade(insulin signalling pathway)


》Large G Proteins refer to the membrane associated heterotrimeric G-proteins that are functionally coupled to seven transmembrane domai recepters(GPCRs)


G-Proteins


Termination of Hormone Action

1.By Extracellular Enzymes:


Many of small ligands for GPCR can be rapidly metablized or inactivatedby extracellular enzumes resulting in termination of hormone action


2.Rapid Desensitisation or Adaptation:


Most receptors exhibit rapid desensitisation or adaptation. Although some ofthis adaptation is due to receptor internalization and down regulation, theprimary mechanismfor rapid GPCR desensitisation involves phosphorylation of cellsurface receptors resulting in loss of function. The phosphorylated receptors can't efficiently activate G proteins


3.Intrinsic GTPase Activity:


The alpha s subunit has intrinsic GTPaseactivity by which it hydrolyzes GTP to GDP and truns itself off. As a reult it dissociates from adenyllyl cyclase, rendering the enzyme inactive and trimeric Gs complex is reformed


>Clinical correlation: cholera toxin mechanism


4.Cycluc Nucleotide Phosphodiesterases:


Another way to terminate hormine action is via cyclic nucleotide phosphodiesterases. These enzymes cause hydrolysis of cAMPto 5'-AMP


>Clinical Correlation: Inhibitors of phosphodiesterases, mlstnota ly methyl xanthine derivatives such as caffeine, inc intracellular cAMP and prolong hormone action


5.Phosphoprotein Phosphatase:


Another means of controlling hormone action involves phosphopreotein phosphatase. This enzyme regulates protein dephosphorylation reactions.

Isoelectric pH

It is the pH at which a particular molecule carries no net electrical discharge

Metabolic Acidosis

Acid accumulation in body due to inc acid ingestion or production or de acid excretion,or GI or renal HCO3- loss


causes BP drops and diarrhoea

Principle of pHmetry

A pH metre measure how acidic or alkaline a liquid is


The basic Principle is to measure the concentration of hydrogen ions in liquid. When an acid dissolves in water, it releases hydrogen ions the number of which determines how acidic the liquid is

Homopolysaccharides


Definition


Types

A polysaccharide composed of only one kind of monosaccharide or on hydrolysis yileds only one type of monosaccharide units


Types


Storage Homopolysaccharides inulin, starch, glycogen


Structural Homopolysaccharides cellulose, chitin

Starch


Definition

Starch is the storage homopolysaccharide in plants. It occurs intracellularly as large clhsters or granules.


Converted to glucose to provide energy to body

Starch


Sources

Most plant cells have ability to form starch but esp abundant in tubers such as potatoes


Other siurces are corn, rice, wheat, bread

Starch


Structure

Homoplymer of glucose, called glucosan or glucan. Its granule has two main constituents:


Amylose: (15-20%)


> long unbranched chains of D glucose residues connected by ą(1> 4) linkages


> a single chain can contain up to 4000 glusose units


> amylose coils up into a helix that repeats after every 6 glucose units


Amylopectin: (80-85%)


> highly branched structure


> gucose residues are joined by ą(1> 4) linkages at straight chain and ą(1> 6) li kages at branch points


> branching occurs after every 24 to 30 glucose residues

Fasting State: amino acids used by Skeletal Muscles

Leucine


Isoleucine


Valine

Muscles LIVe fast

Essential Amino Acids

P henylalanine


V aline


T hreonine


T ryptophan


I soleucine


M ethionine


H istidine


A rginine


L eucine


L ysine

PVT. TIM HALL, always ARG never TIR

Starch


Digestion

》Moist heat causes the intracelleular starch grainsto swell, the cells may disrupt and starch becomes more soluble, hence cooking renders starch more accessible to digestive enzymes


》 Dietary starch is digested in GIT by salivary amylase and pancreatic amylase


》The products are maltose, isomaltose, maltotriose and ą limit dextrins

Limit Dextrins

Any of the small polymers remaining after the exhaustive digestion of glycogen or starch by enzymes that catalyze the removal of terminal sugerresidues but unale to cleave linkages at branch points

Starch


Diagnosis

Iodine(I2) is inserted in middle of amylose helix to give blue colour characteristicof starch

Dextrins

》degradation products of starch in which the glucose chains have been broken down to smaller units by partial hydrolysis


》limits glycemic load of a high carb meal


》beciase its a water soluble carb, it can act as a natural binding agent


》main source of carbs in proprietary preparation used as oral supplements and for tube feeding


》liquid glucose is mixture of glucose, dextrins, maltose and water. These products are means of giving carbs in an easily assimilate form to seriously ill patients


》because dextrin molecules are larges than starch and glucise they have less os otic effects and are thjs less likel to cause osmolar diarrhoea


Dextrans


Features

》bacterial and yeast polysaccharides


》no part in dietetics but used in medicine as plasma expanders


> a 10% solution is given in IV causes an inc in blood volume and consequent inc in cardiac output and renal blood flow in shock patients following hemorrhage


》absorbs water and forms viscous colloidal solution with water

Dextran


Structure

》complex branched polysaccharides


》MW: 40,000. 70,000. 75,000


》made up of ą-1, 6-linked poly-D-glucose


》all have ą-1,3 branches, and some also have ą-1,2 or ą-1,4 branches

Dextrans


Source

Synthesized from sucrose by leuconostoc mesenteroids and streptococcus mutans (products of reaction of glucose and enzyme transglucosidase)


Transglucosidase


[Sucrose]n----------------------------------> dextran + [fructose]n

Dextrans


Uses

1. Larger Dextrans(> 60,000Da), which cant pass out of vessels, are potent osmotic agents and are used as plasma exoanders in treatment of hypovolemic shock


2.occasionally used to replace blood in emergency situations when replacement blood is not available


3.dextran-40 (MW:40,000Da) is used as anti thrombotic or anti platelet agent to reduce blood viscosity in microsurgery


4.some dextrans e.g. sephadex are used as molecular sieves to seperate proteins and other large molecules(size exclusion chromatography)


5. Component of dental plaques

Glycogen


Features

1. Main storage homopolysaccharide in animal cell(animal starch)


2. Present in cells(hepatocytes and muscles) as insoluble granules(clusters of individual glycogen molecules)


3. These granules also contain enzymes responsible for synthesis(glycogen synthase) and degradation(glycogen phophorylase) of glycogen


Glycogen


Test

Glycogen and iodine give red violet colour

Glycogen


Structure

》like amylopectin, glycogen is a polymer of ą(1-4) linked subunits of glucose with ą(1-6) linked branches, but glycogen is more extensively branched (on average, 1 branch per 8to 12 residues) and more compact than starch (more and shorter branches)


》because each branch in glycogen ends with nonreducing suger unit, a glycogen molecule with n branches has n+1 non reducing ends, but only one reducing end


》degradative enzymes act only at the non reducing ends and remove a glucose unit every time


》glycogen ingested in diet is hydrolyzed by ă-amylases (salivary and pancreatic) that break ą(1-4) glycosidic bond

Glycogen


Sources

Meat in diet


Synthesized in body from glucose in the well fed state

Glycogen


Storage

It's stored in muscles and liver. Hepatocytes store a glycogen equivalent to a glucose conc 0f 0.4M. The actual Concentration of glycogen is about 0. 01µM. If cytosol contained o.4M glucose, the osmolartiy would be threateningly high, leading to osmotic entry of water that might rupture the cell.

Glycogen


Biochemical significance


》Liver Glycogen used for maintenance of blood glucose particularly between meals (fasting)


》Muscle glycogen readily available sourvpce of glucose unitsfor production of ATPthrough glycolysis within the muscle itself. Its not used for maintenance ofblood glucose levels becauseof absence of enzyme glucose 6-phosphatase which converts glucose 6-phosphate into glucose which can leave the cell

Inulin

》polysaccharide of fructose found in tubers and roots of dahlias, artichokes and dandelions


》readily soluble in water


》freely filtered and not reabsorbed or secreted by tubular epithelial cells which is why its used to determine the GFR( considered as gold standard for renal function evaluation)

Cellulose


Features

》fibrous tough water insoluble substance that forms the cell wall of plant cells


》particularly found in stems stalks trunks and all woody portions of plants


》most abundant polysaccharide on earth


》in dietary fibre to treat constipation

Cellulose


Structure

Cellulose molecule is a linear branched homopolysaccharide, consiste of 10,000 to 15,000 glucose residues


In contraat to amhllse and glycogen, the glucose reajpidues here are connexted by Beta1-4 linkage which gives it a very different 3 dimensional structure and physical properties from amylose

Cellulose


Digestion

》digested by an enzyme called cellulase


》most animals including humans cant digest cellulose because they lack cellulase to hydrolyze their Beta 1-4 linkages


》termites readily digest cellulose because their intestines harbour a microorganism trichonympha that secretes cellulase


》 wood fungi and bacteria also produce cellulase.


》the o ly verte rates that are able to use cellulose aa food are cattle, sheep, goats, camels, girrafes.

Chitin

》linear homopolysaccharide composed of N-acetylglucosamine residues in Beta-linkage


>only chemical difference from glucose is the replacement of -OH group at C-2 with an acetylated maino grouo


》forms exoskeleton of crustaceans, insects andmushrooms.


》like celulose , chitin is indigestible by vertebrates

Glucose is an epimer of?

Glucose is a C4 epimer of galactose

Mr Gluca has GONe to the cAMP to bring out some Glucose

Glycogen elevates glucose by cAMP mechanism

Vitamin A


Sources

》Retinol


> liver


> eggyolk


> whole milk


> butter


> kidneys


carotenoids


> dark green and yellow orange veggies

Vitamin A


RDA

Adult male 900-1000RE


Adult female 700-800RE


1RE=1µg of retinol or 6µg of beta carotene


Vitamin A


Absorption

》in small intestine, the combined action of bile plus pancreatic esterases hydrolyses retinyl esters


> the products of hydrolysis are fatty acids and retinol


> retinol is actively transported in micellar form across the me branes of epithelial cells of intestinal villi


>intestingal cell absorption of free retinol is folowed by re esterifictaion with long chain FA predominantly stearic and palmitic acid, within the mucosal cells


》Absorption of Beta carotene is very variable


> Bile salts emulsidy itand enhance its uptake by the mucosal cells of small intestine


>within the intestinal mucosal cells, beta carotene is oxidatively cleaved by cellular Beta carotene di-oxygenase(beta-carotene-15, 15'-oxygenase) to yield 2 molecules of retinal


>reduced to retinol


> esterified

Vitamin A


Transport

>Retinol is carried from intestines as retinyl esters (retinyl palmitate) in chylomicrons and taken up by liver


> released from liver as retinol


>circulates in blood bound to specific tranport protein-RBP retinol binding protein

Vitamin A


Storage

>stores as retinyl palmitate in liver where stores are sufficient to meet the requirements for months or even years with no dietary intake


>Retinoyl beta-glucuronide is biologically active water soluble metabolite

Vitamin A


FUCTIONS

1.Role in Vision


2. Regulation of Gene expressiom and tissue differentiation


3. Synthesis of Gkycoproteins for normal Growth Development and mucous Secretion: retinol is converted to retinylphosphate thats essential for noraml growth regulation. Glycoproteins are essential components of mucous


5. Synthesis of Iron Transport Protein Transferrin


6. Noraml bone and teeth development


7. Role in reproduction: for normal spermatogenesis and placental development


8. Beta carotene is an important antioxidant: role in trapping peroxyl free radicals in tussues at low PO2


Vitamin A


Role in Vision

Visual pigment of rod cells:Rhodopsin consists of 11-cis retinal specifically bound to the protein opsin


》 when Rhodopsin is exposed to light, series of photochemical isomerizations occur and theres a relaease of all trans retinal plus opsin


》this generates anerve impulse which is teansmitred via ootic nerve to the brain


Regeneration of Rhodopsin: all trans retinal after being released from opsin, ismoerizedby retinal isomerase to 11-cis retinal, that spontaneously combines with opsin to form Rhodopsin, thus completeing the cycle

Vitamin A


Regulation of Gene Expression and Tissue Differentiation

》retinoic acid controls cell differentiation and turnover


》all trans retinoic acid and 9 cis retinoic acid regulate growth, develooment and tissue differention. They have different function in different body tissues


》retinoic acid binds to hclear receptors rhat are already boundto specific regions of chromatin(response elements) and regulate transcription of specific genes


》there are 2 families of nuclear retinoid receptors


Retinoic Acid Receptors(RARs): bind all trans retinoic or 9 cis retinoic acid


Retinoid X Receptors(RXRs): bind 9 cis retinoic acid

Vitamin A


Deficiency causes

1. Dietary inadequacy


2. Diseases affecting normal lioid digestionand absorptiong


3. Alcoholism

Vitamin A


Clinical Features of Deficiency

1. Night Blindness(nyctalopia)


2. Changes in epithelia


3. Xerophthalmia and kertaomalacia


4. Growth Retardation


6. Poor wound healing


7. Inc susceptibility to Infections


8. Anemia

Vitamin A


Night Blindness

》one of the first indications of deficiency


》occurs when liver stores are nearly exhausted


》visual threshold is inc making it difficult to see in dim light


》prolonged deficincy leads to irreversible loss of visual cells

Vitamin A


Changes in Epithelia

》epithelial cells undego squamous metaplasia


> flattened and heaped upon one another and surface becomes keratinized


》most easilt seen on conjunctiva covering the sclera in xerophthalmia


》follicular hyoermeratosis or Darriers disease:keratinization blocks the sebaceous glands in skin by hirny plugs as retinoic acid downregukates the synthesis of keratin


》affects urovenital, respiratory and GIT but less well amrked there

Vitamin A


Xerophthalmia(dry eye) and Keratomalacia

》Xerophthalmia


>in its mild form its confined to conjunctiva of eye. No disability at this stage but warning signs of deficiency


> corneal xerosis may progress rapidly and suddenly to Keratomalacia


》Keratomalacia softening and dissoltuion of cornea


> when process involves only part of cornea, there is ulceration but inflammatory reaction is mild. Effective treatment at this stage is followed by corneal scaring and opacity


>if process is not stopped by treatment, perforation of cornea leads to prolapse of iris, protrusion of lens and infection of whole eye ball. Chances of savingany useful vision are rare. Healing results in scarring kfwholeeye and frequently total blindness

Vitamin A


Therapeutic Uses

1. To trwat vit A deficiency


2. Retinoic acid and derivatives are hsedto treat sking problems such as aging, acne and psoriosis


3. Retinoic acid and derivatives used in treatment of promyelocytic anemia

Vitamin A


Toxicity


Ingestion of excess vit A or side effects of inappropriate therapy


》Hypervitaminosis A excess intake. Manifestations include dry skon, enlargement or cirrhosis of liver, raised intracranial pressure, inc fracrure risk due to dec bone density


》Teratogenic Effects potential for causing congenital malformations in developing fetus in preggo women. Most serious include fetal resorption, abortion, birth defects, permannentlearning disabilty


》Isotretinoin(13-cis retinoic acid) teratogenic drug. Absolutely contradjcted in women with child bearing potential I kess in case of severe disfiguring cystic acne unresponsive to standard therapies. Pregnancy exclhded before I itiation of treatment and proper birth control applied. Prolonged treatment leads to hyperlipidimea and jnc LDL/HDL ratio hence concern for inc risk of cardiovascular disease


》Hyperkeratonemia from chronic excessive intake of carotene rich food e.g tomato carrot juice. Characterized by jaundice like yellowing kf sking and high plasma carotenoid concentration. Benign confpdition because excessive carotene is deposited rather than converted to vit a. Skin reverts to normal colorafter changing to normal diet

Importance of Pentoses

Important in nucleotides, nucleic acids and several coenzyme

Glycoproteins

》also called mucoproteins


》proteins containing branched or unbranched oligosaccharide chains


》occur in cell membrane and ither situations. Serum albumin is a glycoprotein


Sialic acids are N- or O- acyl derivatives of neuraminic acid


> Neuraminic acid is 9C suger derived from mannosamine(epimer of glucosamine) and pyruvate


> sialic acids are constituents of glycoproteins and gangliosides

Acetylation

Conversion of pantothenic acid to succinyl coA

Phohphatidyl serine function

Rolein apoptosis(programmed sell death)

Other products of Auto Oxidation or Enzymic Oxidation

Other products of physiologic significance are


>Oxysterols: formed from cholestrol


>Isoprostanes:formed from peroxidation of polyunsaturated FA such as arachidonic acid

Vitamin D


As a Steroid Prohormone


》cholecalciferol is synthesized in the body in skin


》its converted to 1,25-diOHD3(calcitriol) by various metabolic changes


>calcitriol is a hormone like substance that acts on distant organs e.g, kidneys gut bones, and its receptors resembles thlse for retinoic acid and thyroid hormones

Vitamin D


Chemistry

Vit D is a generic term for 2 molecules:


1. Cholecalciferol(vit D3): natural form


>produced by UV irradiation(290-312nm) of 7-dehydrocholestrol, a sterol found in animals. Uv irradiation cleaves its B ringin dermis and epidermis of humans exposed to sunlight


> rate of synthesis in skin is determined by:


1. Degree odpf expksure to UV light


2. Amount of pigment: a heavily pigmented child is more susceptible to rickets because melanin reduces penetration of UV light


3. Latitude: short UV wavelengths of light reuired for the photoconversion of 7-dehyrocholestrol are absorbed as they pass through the atmosphere


2. Ergocalciferol(vit D2): manufactured form


> widely used in therapeutics


> manufactured by exposing ergosterol, sterol in fungi and yeast, to action of UV light. UV irradiation cleaves it B ring.



Comparison


> differ only in side chain:extra methyl group at C24 and a double bond betwen C22 and C23 in ergocalciferol


> both have equal potency and undergo same hydroxylations in body


Vitamin D


Active form

》D2 and D3 are not biologically active but converted in vivo to active form 1,25-diOHD3 by 2 sequential hydroxylation reactions


》calcitriol is considered hormone because ts produced in body and transported to target organs where it initiates biologic processes in a manner simikar to steroid hormones

Vitamin D


Sources

A.Endogenous sources


D3 produced in skin


B. Exogenous(dietary) Sources


>D3: obtained from saltwater fish e.g. sardines, salmon, herring


Egg yolk


Liver


Only rich sources are liver oils of fish


> D2: milk butter and other foods routinely fortified with vit D2

Vitamin D


RDA

>as long as body is exposed to adequate sunlight, theres little to no dietary requirement


>Adult:5µg of cholecalciferol or 200IU of vit D

Vitamin D


Absorption


Transport


Storage


Synthesis of calcitriol


Excretion

》D3 forned from 7-dehydrocholestrol by action of su light ks transferred to specific vit D binding plasma protein


》Dietary vit D2 or D3, after Absorption From small intestine is carroed in chylomicrons to liver


》D, of cutaneous or dietary origin istaken up by liver where its hydroxylated at 25th postion by 25-hydroxylase (ER enzyme). 25-OHD3 is major form of Vit D I circukation and is transported witn vit d binding globuling


>25-OHD3 is major Storage form in liver, adipose tissue and skeletal muscle have also been reported as major storage sites


>a sig ificant fraction of 25-OHD3 enters enterohepatic circulation and disturbance of this process can lead to vit D deficiency


》in renal tubules, placenta and bones, 25-OHD3 is further hydroxylated at postion 1 by 1-hydroxylase (mitochondrial enzyme)>Product is 1,25-diOHD3(calcitriol)>most potent vit D metabolite


>production regulated by own concentration, parathyroid hormone and serum phosphate


》25-OHD3 can also be hydroxylated at postion 24 by 24-hydroxylase (mitochondrial enzyme), present in renal tubules, cartilage, placenta and intestines


> level of this product is reciprocally relatedto level of 1,25-diOHD3 in serum


> biologically inactive


》High PTH level stimulate 1,25-diOHD3 formation


Low PTH levels: 24,25diOHD3 formation


》Vitmain D is excreted in bile as more polar hydroxylated metabolites and some in form of glucuronides

Vitamin D


Mechanism Of Action

Active form 1,25-diOHD3 binds to intracellular receptors(nuclear receptors already bound to DNA)→1,25-diOHD3-receptor comolex is formed→1,25-diOHD3-receptor comolex on specific regions of DNA inc transcription of specific genes in nucleus of target cells e.g. intestinal epithelial cells→inc transcription of specific genes→inc mRNA→specific genes are synthesized e.g calcium binding proteins

DNA bond Strength between nucleotides

Strongest 3 H bonds between Cysteine and Guanine


Weaker 2 H binds between A and T which is where the RNA primer will break

Enzyme Kinetics:Competitive vs Non Competitive

Kompetitive Inhibiton: Km Inc, no change in Vmax


Non Kompetitive: No change in Km , Vmax dec

Sickle cell anemia

At 6th postion of HB beta chain , valine is present instead of glutamic acid

HBs isnt very good

Vitamin D


Mechanism involved in Intestinal Calcium Absorption and Renal Calcium Reabsorption

Intestinal Calcium Absorption


> Ca is transported across brush border of intesinal epithelial cells via channels caled Transient Receptor potential Vanilloid Tyoe 6 (TRPV6)→ Ca then binds to intracellular proteins called Calbindins→they sequester Ca so it doesnt interfere with the signalling process in epithelial cells thats involves Ca→ Absorbed Ca is deliveredtobasolateral membrane of epithelial cells→ transpored into blood stream by either a sodium/calcium exchanger(NCX1) or Calcium deoendant ATPase


Renal Calcium Reabsorption


> Plasma Ca is filtered in kidneys but 98-99% of filtered Ca is reabsorbed. About 60%of reabsorption occurs in proximal tubules, remainder in ascendimg limb of loop of henle a d distal tubules


> proxiaml tubular(expression inc in calcitriol presence) and distal tubular(regulated by PTH) reabsorption involves GRPV5 channels

Vitamin D


Functions

1,25-diOHD3 fuctions aa hormone and along with calcitonin and PTH , regulates Ca and P metabolism


1. 1,25-diOHD3 inc Intestinal absorption of Ca and P


2. 1,25-diOHD3 facilitates Ca reabsorbtion in kidneys: via inc TRPV5 expression in proximal tubukes


3. 1,25-diOHD3 helps in mineralization of bones


4. Inc mobilization of bones when theres Hypocalcemia


5. Insulin secretion


6. Synthesis and secretion of parathyroid and thyroid hormones


7. Inhibition of production of Interleukins byactivated T lymphocytes and of immunoglobulin by activated B Lymphocyte


8. Differentiation of Monocyte precursor cells


9. Modulation of Cell Proliferation

Vitamin D


1,25-diOHD3 Increases Intestinal absorption of Ca and P

》acts as typical steroid hormone in intestinal mucosal cells where it induces synthesis of specific proteins plus inc no. Of following ontestinal cells:


1. TRPV6 molecules


2. CalbindinsD9kand CalbindinsD28k


3. Calcium-ATPase


Consequently overall capacity for absorption of dketary Ca is inc


》facilitate P absorption by stimulating a seperta P transport mechanjsm in intestinal epithelial cells

Vitamin D


1,25-diOHD3 hekos in Mineralisation of Bones

1. Intestinal Ca absorotion and renal Ca reabsorption provides adequate solubilty product (CaXP) for vit D to mineralize bones. Hydroxyapatite is the crystalline salt deposited in bones


2. Inc synthetic activity of osteoblasts is necessary for normal calcification of matrix


3. Enhances hydrolysis of an inhibitor of mineralization, thus promoting calcification in presence of 1,25-diOHD3 alkaline phosphate hydrolyzes phospatase


Vitamin D


Inc Mobilisation of calcium from bones when theres Hypocalcemia

>bone resorption occurs when theres dec olasma Ca and high levels of PTH


>In bines, 1,25-diOHD3 and PTH acts synergistically to promote bone resorption or demineralization by stimukating formation and activity of osteoblasts. Stimulation of osteoblasts brings about secondary inc in activity of osteoclasts

Vitamin D


Response to Low Plasma Calcium

Vitamin D


Deficiency Causes

1. Dietary inadequacy


2. Insufficient exposure to sunlight


3. Defects in enterohepatic circulation of 25-OHD3

Vitamin D


Manifestations of Deficiency


1. Nutritional Rickets and Osteomalacia


2. Renal Rickets(Renal Osteodystrophy)


3. Hypoparathyroidism

Vitamin D


Nutritional Rickets and Osteomalacia

》Immediate effect is reduced intestinal absorption of Ca→reduces plasma Ca concentration→PTH released, becahse maintenence of blood Ca levels is top priority


》Even in long term vit D deficiency plasma Ca can bemaintained at nearly normal levels by PTH, at expense of bones which are gradualldy drained of their mineral content


>affected children have soft cartilaginous bones that bend easily


>affected adults have brittle bones that break easily


Rickets (twisting)


>characterised by continuous formation of collagen matrix of bones but mineralization is incompletr→soft pliable bones


Osteomalacia (softening of bones)


> demineralization of pre existing bones→bones become brittle, more susceptible to fractures, maybe bowing of legs

Vitamin D


Renal Rickets


Cause: chronic renal failure


Affected subjects are unable to form active form of vit D


Treatment: 1,25-diOHD3 replacement therapy


Vti D supplementation is accompanied by phosphate reduction therapy to prevent hyperphosphatism(due to renal failure) and precipitation of calcium phosphate crystals

Vitamin D


Hypoparathyroidism

>lack of PTH causes hypocalcemia and hyperphosphatemia


> patient mahbe treated with calcitriol and Ca supplementation

Vitamin D


Toxicity

Most toxic of all vits


Hypervitaminosis D:


>caused by overuse of vit D supplements


>high doses (100,000 IU for weeks or months) can cause loss of apetite, thirst, nausea, vomiting, stupor, hypercalcemia(because of enhanced calcium absorption and bone resorption), hypercalciuria, metastatic calcification(abnormal calcification of soft tissues e.g arteries ad kidneys)


》some infants are sensitive to intakes of vit D as low as 50µg/day resulting in elevated plasma Ca conc→leads to contraction of blood vessels, calcinosis, high BP


》Excess DIETARY vot D is toxic but excess exposure to su light doesnt cause vitD poisoning due to limited capacity to form the precursor 7-dehydrocholestrol andprolonged exposure of vit D to su light leads to formation of inactice compounds


Increase In serum calcium level caused by?

Both PTH and vit D

Calcitonin

Thyroid hormone


Dec blood Ca by ihibiting mobilization from bone and reabsorption from kidney


Vit D deficiency dec secretion of calcitonin

Vitamin D


UL

200IU per day


AL for vit D is 200IU till age 50 and 400to 600IU after age 50

Enzymes


Classification

O xidoreductases


T ransferases


H ydrolases


I somerases


L yases


L igases

OVer The HILL

Purine produces?

Uric acid

RNA structure

The linear array of nucleotides in RNA consists of A, G, C, U and the sugar moiety is ribose

Simple Proteins

On hydrolysis yield only the amino acids and an occasional carb compound


Examples: albumin, albuminoids, globulin, glutelins, histone, protamines

Collagen


Basics

》most abundant protein in body


》a typical molecule is a long rigid structure in which 3 polypeptides or ą chains are wound around each other in a rope like triple helix


》in EC matrix and vitreous humor of eye, its dispersed as gel that gives support to the structure


》in tendons, its bundled in tight parallel fibres thay give great strength


》in cornea, its stacked so aa to transmit light with minimum scattering


》in bones, the fibres are arranged at angles to each other to resist mechanical shear from any direction

Collagen


Types

》3 polypeptide ą chains are held together by interchain hydrogen bonds approx 1000 amino acids in length


》variations in amino acid sequence of ą chains results in structural components with approx same size but slightly different properties


》the most common collagen type 1 has two ą1 chains and one ą2 chain (ą1`2`ą2). Type ll contains three ą chains(ą1`3`)


》the collagens can be organised into 3 groups based upon their location and function


1. Firbril forming Collagen


> type l, ll, lll


> rope like structure


> type l are found in supporting elements of high tensile strength


>type ll are restricted to cartilaginous structure


>type lll are prevalent in more distensible tissues


2. Network forming Collagens


>type lV and Vlll


>form 3 dimensional mesh


3. Fibril associated collagens


> type lX, Xll


>FACITs


> bindto surface of collegen fibres linking them to each other and to other components of extracellular matrix

Basement membranes

》type lV network forming collagen


》thin sheet like structures that provide mechanjcal support for adjacent cells


》fuction as semi permeable filtration barriers to macromolecules in organs such as lungs and kidneys


Collagen


Structure

1. Amino Acid Sequence:


> rich in glycine and proline which are important in formation of triple stranded helix


>Proline Facilitates the formation of helical conformation of each ą chain because its 4ing structure produces kinks in peptide chain. Its presence dictates that helical conformation of ą chain cant be an ą helix


>Glycine smallest amino acid. Fou d in every 3rd positon of polypeptide chain. Fits into the restricted spaces where the 3 chains of helix come together. Glgcine residues are lart of a repeating sequence, -Gly-X-Y-, where X is frequently proline and Y is often hydroxyproline or hydroxylysine


>thus most of ą chain can be regarded as polytripeptide whose sequence can be represented as (-Gly-X-Y-) 333



2. Triple Helical Structure:


This fibrous protein has an elongated triple helical structure thats stabilized by interchain hydrogen bonds



3. Hydroxylysine and Hydroxyproline:


>not present in most other proteins


>these residues result from the hydroxylation of some of of the proline and lysine residues after their incorporation I to the polypeptide chains


>this hydroxylation is thus an example of pkst translational modification


>generation of hydroxyproline maximizes the interchain hydrogen bonds that stabilize the triple helical structurr



4. Glycosylation:


>hydroxyl group of hydroxylysine residues of collagen maybe enzymatically glycosylated


>most commonly glucose and galactose are sequentially attached to polyoeptide chain prior to triple helix formation

Collagen


Biosynthesis

The polypeptide precursors of collahen milecules are synthesized in fibroblasts. Theyre enzymically modified and form the trioke helix which gets secreted into extracellular matrix. After further enzymic modification, the mature extracellular collagen monomers agregate to become the collagen fibres.


1.Formation of pro-ą chains


2. Hydroxylation


3. Glycosylation


4. Assembly and secretion


5. Extracellular cleavage of procollagen molecules


6. Formation of collagen fibrils


7. Cross link formation

Collagen


Biosynthesis


Formation of pro-ą chains

Colagen functions outside of cell so newly synthesised prepro-ą chains contain a soecial amino acid sequence at their Nterminal ends→this sequence acts as a signal to target the polypeptide being synthesised for excretion from cell→signa sequence facilitates binding of ribosomes to RER and directs the passageof prepro-ąchains into lumen of RER→signal sequence is rapidly cleaved in RERto yield a lrecursor of collagen called pro-ą chain

Collagen


Biosynthesis


Hydroxylation

》pro-ą chains are processed by a number of enzymic sgeps withing RER lumen→proline and lysine residues in the Y position of -Gly-X-Y- sequence are hydroxylated to form hydroxyproline and hydroxylysine residues


》the hydroxykatio requires molecular oxygen, Fe2+, and reducing agent vit C for the enzymes prolyl hydroxylase and Lysyl hydroxylase to function


》Scurvy


> ascorbic acid deficiency→lack of proline and lysine hydroxylation→impaired interchain H bond formation→impaired formation of stable triple helix→collagen fibrils cant be crosslinked→dec tensile strength of assembled fibres


>patients also show bruises on limbs due to subcutaneous bleeding from capillary fragility

Collagen


Biosynthesis


Glycosylation

Some hydroxylysine residues are modified by glycosylation with glucose or glucosyl-galactose

Collagen


Biosynthesis


Assembly and Secretion

>after hydroxylation and glycosylation, three pro-ą chains form procollagen, precursor of collagen with a central region of triplehelix flanked by the non helical amino and carboxyl terminal extensions called propeptides


> formation of procolagen begins with interchain disulfide bonds between C-terminak extensions of pro-ą chains→this brings the 3 ą chains into an alignment favourable for helix formation→procollagen molecules move through golgi apparatus where theyre packed on vesicles which fuse with cell membrane causing release of procollagen molecules into extracellular matrix

Collagen


Biosynthesis


Extracellular cleavage of procollagen molecules

Procollagen molecules are cleaved by N and C-procollagen peptidases which remove the terminal propeptides, releasing triple helical tropocollagen molecules

Collagen


Biosynthesis


Formation of Collagen Fibrils

Tropocollagen molecules form an ordered overlapping parallel array with adjacent collagen molecules arranged in a staggered pattern

Collagen


Biosynthesis


Cross link Formation

The fibrillar array of collagen molecules serve as a substrate for lysyl oxidase( Cu2+ containing extracellular enzyme) →oxidatively deaminates some of lysine and hydroxylysine residues in collagen→the resulting reactive aldehydes, allysine and hydroxyallysine, can condense with lysine or hydroxylysine residues in neighbouring collagen to form covalent cross lonked mature collagen fibres

Collagen


Degradation

Collagen is highly stable but connective tissue is dynamic and constantly remodelled in response to growth and inury. Breakdown ofcollagen fubres is dependant on proteolytic action of collagenases


For type l the cleavagesite is soecific, generating 3 quarters and1 quarter length fragments which are further degraded by ither matrix Proteinases

Collageniopathies

1. Ehlers danlos syndrome


>Heteroge oudps group of connective tissue disorders that reuslt from inheritable defects in metabolism of fibrillar collagen molecules


> can becajsed by deficiency of collagen processing enzymes e.g. lysyl hydroxylase, N procollagen peptidase, or from mutations in amino acid sequences of collaen tyoe l, lll or V


> classic form: defecta in type V, skin extensibility and fragility and joing hypermobility


> vascular form: defects in type lll collagen, pktantiallt lethal arterial rupture


>dominant negative effect: incorporation of just one mutant chain may result in degradation of triple helix



2. Osteogenesis imperfecta


> brittle bone disease, bone fracrure by little or no trauma


>mkstly caused by dominant mutations to genes that ckde for ą1 or ą2 chains in type l collagen


>most commkn mutations cause replacement of glycine in sequence by amino acids with bulky side chains and the resultant structurally abnormal ąchains lrevent formation of triple helical conformation


>type l OI mkst common, mild bone fragility hearing loss, blue sclera


>type ll lethal in perinatal period due to pulmonary complications, in utero fractures


>type lll, multiple fractures at birth, short stature, spinal curvature leading to humped back and blue sclera, dentinogenesis imperfecta

Vitamin E


Chemistry

》there are 8 naturally occuring vitamin E compounds


》synthesized by plants from homogentisic acid


》all have a chromanol ring attached to a hydrophobic side chain


》there are 2 families:


> Tocopherols: chromanol ring is attached to saturated 16C phytol side chai alpha tocopherol (5,7,8-trimethyl tocol) biologically most active form , widest natural distribution


> Tocotrienols: chromanol ring attached to unsaturated 16C phytold side chain. 3 double bonds


Both are further divided into alpha beta gamma and delta forms depending upon presence of -H or -CH3 on R2 and R2 positions

Vitamin E


Properties

>viscous oil at room temperature


>insoluble in wate, soluble in fat solvents


>stable to heat and acid


Vitamin E


Sources

>abundant in veggies, fruits, grains


Vegetabke oils are rich natural sources


Wheat germ oil has highest conc


>liver and egg yolk contain moderate amounts

Amino acids with uncharged polar groups

Methionine


Asparagine


Glutamine


Cysteine


Threonine


Serine

MAG CYSTS

Quarternary Structure of Proteins

Tetramer→2 identical dimers→polypeptide chains in each dimer are held tightly by hydrophobic interactions(may be H bonding or ionic)→two dimers are held together by polar bonds and able to move with respect to each other


>many proteins consist of a single polypeptide chain and are called monomeric proteins


>others consist of two or more polypeptide chains that may be structurally identical or completely unrelated. The arrangement of these polypeptide subunits is called quarternary structure of proteins


>subunits are held together by primarily by non covalent interactions e.g.hydrogen, ionic hydrophobic


>subunits may either function independently or work cooperatively as in hemoglobin where binding of oxygen to one subunit of tetramer inc the affinty of all subunits for oxygen

Isoforms

Proteins that have same function but different primary structure. They can arise from different genes or from tissue specific processing of products of same gene

Isozymes

If proteins function as enzymes

Vitamin E


RDA

Adult male: 10mg ą-TE


Adult female: 8mg ą-TE


1 mg ą tocopherol= 1 ą-TE


Requirement for tocopherol increases if theres increased uptake of polyunsaturated fatty acids

Vitamin E


Storage

Adipose tissue

Vitamin E


Free Radicals

》an atom or molecule having one ofpr more unpaired electrons


》consequent tendency to acquire electrons from abother substance renders it highly reactive


》studies suggest that reactive free radicals might be involved in diseases such as heart diseases and cancer and antioxidants preventing the free radical reactions may play important role in modifying the development of these diseases


》examples: superoxide free radical, peroxide free radical, hydroxyl free radical

Hemoglobin binding curves


Causes of shift to right

CO2


Acid


2,3-BPG


Exercise


Temperature

CADET turn right

Vitamin K dependant cofactors

Seven


Ten


Nine


Two


Protein S and C


Several tend to Nicely stop Clotting

Hereditary spherocytosis cause

Defects in spectrin and ankyrin

Vitamin E


Functions


1. Major lipid solubke antioxidant in cell membrane


Prevents non enzymic oxidation of cell membrane components by molecular oxygen or free radicals. Theres 1 vit E molecule for every 200 phospholipids which suggests that ita rapidly regenerated, possibly by vit C


2. Major lipid solubke antioxidant in plasma lipoprotein


3. Protective effect in membranes of organelles

Vitamin E


Mechanism of action

》example of phenolic antioxidant. Such molecules dreadily donate their H from -OH grouo in ring structure to free radicals→free radical becomes non reactive but phenolic compounds themselves become free radical→unoaired electron is delocalized into aromatic ring structure, stabilizing it so thisfree radical is relatively unreactive


》antioxidant action of tocopherol is effective at high oxygen concentration so it tends to be concentrated in thise lipid structures that are exposed to high PO2 e.g. erythrocyte membrane, membranes of brinchial tree and retina

Vitamin E


Deficiency

Causes


Common in lremature and low birth weight babies


Associated with fat malabsoprtion in adults


Manifestation


Irritability, edema, hemolytic anemia

Vitamin E


Toxicity

Least toxic of all fat soluble vits

MS Method

>largly replaced by edman method


>sensitive and versatile method to determin primary structures, posttranslational modification and for detecting metablic abnormalities

O2 Binding Curves

>O2 binding curve for myoglobin is hyperbolic


>sigmoidal for hemoglobin because of cooperative interactions in tetramer which max its ability to load O2 at PO2 of lings and to deliver O2 at PO2 of tissues

Macromolecules and Micromolecules

Macromolecules: large intakes of these energy rich molecules, fats, carbs, proteins and in some diets, ethanol


Micromolecules: nutrients required in small amounts, vitamins and minerals


Essential nutrients in Diet

Location of Polar and Non Polar amino acids Residues in Myoglobin

> Non polar amino acids: present in the interior of myoglobin molecule, packed closely together, forming a structure stabilized by hydrophobic interactions between the clustered amino acids


> Polar Amino acids: present almost exclusively on the surface where they form hydrogen bonds, both with each other and with water molecules

Dietary Reference Intakes DRI

>estimates of the amounts of nutrients required toprevent deficiency and maintain optimal health and growth


>establishes upper limit on the consumption of some nutrients and incorporates their roles in long term health


>consists of 4 dietary reference standards for nutrient intake designated for specific age groups, physiologic states and genders

Estimated average Requirement-EAR

the average of daily nutrient intake level estimated to meet the requirements of one half of healthy individuals of specific life stage and gender group is the EAR. Useful in estimating the actual requirements in groups and individuals

Recommended Dietary Allowance- RDA


>Average daily dietary intake level thats sufficient to meet the nutrient requirements of nearly all indidviduals of a lifa stage or gender group


>not the minimal requirement for healthy individuals but rather set to provide a marhin of safety for most individuals


>the EAR serves as a foundation for setting RDA. If the Standard Deviation of EAR is available and the nutrient requirement is nirmally distributed, the RDA is set at 2 SDs above the EAR


>RDA=EAR+2SD'EAR'