Q. Absorption of the iron. Proteins of the iron transport and storage




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CELL AND ORGAN:


Q. Absorption of the iron. Proteins of the iron transport and storage


Ans.


Iron absorption occurs predominantly in the duodenum and upper jejunum. The mechanism of iron transport from the gut into the blood stream remains a mystery despite intensive investigation and a few tantalizing hits. A feedback mechanism exists that enhances iron absorption in people who are iron deficient. In contrast, people with iron overload dampen iron absorption.


The physical state of iron entering the duodenum greatly influences its absorption however. At physiological pH, ferrous iron (Fe2+) is rapidly oxidized to the insoluble ferric (Fe3+) form. Gastric acid lowers the pH in the proximal duodenum, enhancing the solubility and uptake of ferric iron. When gastric acid production is impaired (for instance by acid pump inhibitors such as the drug, prilosec), iron absorption is reduced substantially.


Heme is absorbed by machinery completely different to that of inorganic iron. The process is more efficient and is independent of duodenal pH . Consequently meats are excellent nutrient sources of iron. In fact, blockade of heme catabolism in the intestine by a heme oxygenase inhibitor can produce iron deficiency (Kappas et al., 1993). The paucity of meats in the diets of many of the people in the world adds to the burden of iron deficiency.


iron transport is based on identification of iron binding proteins at several key sites. They propose that mucins bind iron in the acid environment of the stomach, thereby maintaining it in solution for later uptake in the alkaline duodenum. According to their model, mucin-bound iron subsequently crosses the mucosal cell membrane in association with integrins. Once inside the 

cell, a cytoplasmic iron-binding protein, dubbed "mobilferrin", accepts the element, and shuttles it to the basolateral surface of the cell, where it is delivered to plasma. In this model mobilferrin could serve as a rheostat sensitive to plasma iron concentrations. Fully occupied mobilferrin would dampen mucosal iron uptake, and while the process would be enhanced by unsaturated mobilferrin. 


Q. Adhesion and aggregation of platelets


Ans.


Platelet adhesion is the initial step in the formation of the hemostatic plug. When injury occurs to the endothelium, platelets escape from the blood vessel. Under the high shear flow stress at the site of injury, they come in contact with and adhere to subendothelial tissues. Platelets immediately begin to adhere with the help of vWF, forming bridges or connections between platelet surface molecule glycoprotein Ib and components on the subendothelium (mostly collagen fibers). This process continues with attachment of platelet receptors to several adhesive proteins in the matrix of connective tissue. Other platelets spread in a similar fashion, covering the collagen surface with a single layer of platelets.


Following platelet activation, formation of the primary hemostatic plug continues with platelet aggregation. This is the phase in which activated platelets become attached to one another.1 After the release of agonists such as adenosine diphosphate (ADP), by platelets and the injured vessels, platelets undergo a change in shape and glycoprotein IIb/IIIa receptor sites become exposed. These changes enable the activated platelet to stick readily to those adhering to collagen. Aggregation takes place in two phases. In the primary phase, platelets attach loosely, and if the agonist stimulus is weak, they can be separated. The secondary phase requires a longer period of time in which platelets release their own ADP, further stimulating the aggregation process.


Q. Biochemical explanation of the steroid-induced transciptional activation


Ans.


An inactive nuclear receptor is found in the cytoplasm of the cells. It complexes with heat shock proteins that keep the receptor inactive but sensitive for activation.


Free (unbound) steroids enter the cell's cytoplasm and interact with their steroid receptor. In this process, heat shock proteins dissociate from the receptor and the activated receptor-ligand complex is translocated into the nucleus. After binding to the ligand (steroid hormone), steroid receptors dimerize.


In the nucleus, the complex acts as trnascription factor as it can bind DNA and palindromic sequences, augmenting or suppressing transcription of particular genes by its action on DNA. 


Q. Biochemical interpretation of the acut phase reaction


Ans.


The term acute phase response summarizes a number of very complex endocrine and metabolic or neurological changes observed in an organism, either locally or systemically, a short time after injuries or the onset of infections, immunological reactions, and inflammatory processes (see also: Neuroimmune network). Each form of injury or tissue disorder that precipitates an inflammatory response inevitably also causes an acute phase reaction (see also: inflammation, wound healing).


An acute phase reaction is characterized, among other things, by fever, and an increase in the numbers of peripheral leukocytes, in particular an increase in the numbers of circulating neutrophils and their precursors. At the same time one observes cellular and biochemical alterations, in particular the coordinated synthesis of so-called acute phase proteins (APP) or acute phase reactants (APR) by hepatocytes in the liver.


The acute phase reaction is initiated and mediated by a number of cytokines with inflammatory activities secreted by a variety of cell types (polymorphonuclear leukocytes, fibroblasts, endothelial cells, monocytes, lymphocytes etc.). The cascades of inflammatory cytokines in different tissues represent amplification and regulatory pathways controlling the development of acute phase responses in vivo. Therefore, this reaction is a direct consequence of the biological activities of an organism's own mediator substances and not the result of intrinsic properties of the infectious and/or inflammatory agents per se.


Q. Biochemical interpretation of the cell cycle and its regulation. The M phase kinase


Ans.


The concentration of cyclins rise and fall in a regular pattern during the cell cycle. A pattern that enables them to turn on, at the appropriate moment, enzymes called cyclin-dependent kinases, whose activity is needed to propel cells through the cell cycle, to undergo several discrete transitions. cyclin oscillations are determined partly by transcriptional ontrol of mRNA production and partly by specific proteolysis mediated by specific ubiquitin ligases. Another layer of control elements are CDK inhibitors (CKI's). 

The 3 stable states of the somatic cycle are:

1- pre start interphase

2- post replication interphase

3- metaphase


A cell cycle consists of 4 phases: G1, S, G2, M


The cyclins with their CDKs move cells through the cycle until they divide in M phase. During G1 there exists a period of low CDK activity due to the presence of CKI's and the lack of transcription of cyclin genes. Synthesis of Cdc6 protein during this period promotes the binding of Mcm proteins to chromatin and the cells assemble a pre-replication complex at future origins of replication.


Activation of S-phase CDK's triggers the firing of origins that had previously formed pre-replication complexes. Replication produces pairs of sister chromatids that are attached to eachother; they can be aligned on the metaphase plate once activation of M-phase CDK'S promotes the formation of the mitotic spindle. M-phase CDK's also promote activity of the anaphase-promoting complex (APC) which leads to loss of sister chromatid cohesion and to destruction of M-phase cyclins. The APC remains active during subsequent G1 period and is turned off by the accumulation of G1-CDK's.


Cyclin A or B bind to mitotic CDK. The key substrates of Cdc2 kinase include: H1 histone, lamins, centrosomal proteins, vimentin and caldesmon. Phosphorylation of lamin is important for the destruction of the nuclear membrane. 

Cdc2 (cdk1) phosphorylates histones, lamins, and microtubule associated proteins (MAP - for chromosomal condenstaion). It also phosphorylates vemntin and caldesmon (for cytoskeletal rearrangement and for the breakdown of nuclear envelope). Finally, cdc2 promotes the activity of APC. APC degrades cyclin B which leadss to the shutting down of the M-cdk so anaphase can take place


Q. Biotransformation: definition, detailed description of conjugation reactions (3 examples), origin of conjugated compounds


Ans.


Biotransformation is the chemical modification (or modifications) made by an organism on a chemical compound. If this modification ends in mineral compounds like CO2, NH3+ or H2O, the biotransformation is called mineralisation. Biotransformation means chemical alteration of chemicals such as (but not limited to) nutrients, amino acids, toxins, or drugs in the body. It is also needed to render nonpolar compounds polar so that they are not reabsorbed in renal tubules and are excreted.


Phase II reaction


    * These reactions involve covalent attachment of small polar endogenous molecule such as glucuronic acid, sulfate, or glycine to form water-soluble compounds.


    * This is also known as a conjugation reaction.


    * The final compounds have a larger molecular weight.

Phase II reactions are conjugation reactions - covalent linkage of the absorbed chemicals, or of the products of the phase I reactions, with compounds such as glutathione, glucuronic acid, or amino-acids.


The conjugates produced are generally more water soluble than the chemicals from which they are derived and so are more easily excreted.


Chemicals which undergo phase I and phase II reactions are normally those which are fat soluble (lipophilic).


Fat soluble substances tend to accumulate in body tissue and milk if not converted to an excretable form.


Excretion of conjugates mostly occurs in the bile.


Some conjugates may be broken down to components by bacteria in the gut; the components may again be absorbed and go through phase II reactions; this process is called enterohepatic circulation.


Enterohepatic circulation slows excretion of the substances involved and must be allowed for in evaluating the likely effects of any potentially toxic substances.


Q. Degradation and excretion of heme (steps, enzymes, localization)


Ans.


Most of the heme which is degraded comes from hemoglobin.


Heme is degraded in two steps to bilirubin, which is conjugated to glucuronic acid and excreted.


The first reaction is cleavage of the heme ring by a microsomal heme oxygenase.


The substrates for the reaction are


    * heme

    * three molecules of oxygen

    * NADPH


The reaction is a cleavage of the ring between the I and II pyrrole rings:     * 


The alpha-methylene group is released.

    * The product is symmetric with respect to the propionic acid groups.


The products are:


    * biliverdin

    * carbon monoxide (this is the only endogenous source of carbon monoxide)

    * iron (II)

    * NADP+


In the second reaction biliverdin reductase reduces the central methene bridge of biliverdin, producing bilirubin.


Conversion of biliverdin to bilirubin requires NADPH as a reducing agent.


Bilirubin is highly lipid soluble. This property determines its behavior and its further metabolism.


Several diseases are associated with hyperbilirubinemia. Direct and indirect bilirubin values are used in the differential diagnosis of hyperbilirubinemia


Q. Factors influencing the oxygen binding of hemoglobin


Ans.


1) Carbon Monoxide - CO binds to hemoglobin with a higher affinity than oxygen.  As a result, CO destroys hemoglobin's ability to transport and release oxygen throughout the body.  If exposed to too much CO for too long, a person will likely die due to the lack of oxygen be transported to the brain.


2) Sickle Cell Anemia - A sickled red blood cell is caused by a mutation that substitutes a problematic amino acid in either the alpha or beta polypeptide of a hemoglobin.  This mutation results in an irregular shaped red blood cell due to hemoglobin forming long rods when giving away oxygen.  


Q. Fibronectins and fibronectin receptors: their structure and biological significane


Ans.


Fibronectin exists as a dimer, consisting of two nearly identical polypeptide chains linked by a pair of C-terminal disulfide bonds. Each fibronectin monomer has a molecular weight of 230-250 kDa and contains three types of modules: type I, II, and III. All three modules are composed of two anti-parallel beta-sheets; however, type I and type II are stabilized by intra-chain disulfide bonds, while type III modules do not contain any disulfide bridges. The absence of disulfide bonds in type III modules allows them to partially unfold under applied force.


Fibronectin has numerous functions that ensure the normal functioning of vertebrate organisms.[1] It is involved in cell adhesion, growth, migration and differentiation. Cellular fibronectin is assembled into the extracellular matrix, an insoluble network that separates and supports the organs and tissues of an organism.


Fibronectin plays a crucial role in wound healing. Along with fibrin, plasma fibronectin is deposited at the site of injury, forming a blood clot that stops bleeding and protects the underlying tissue. As repair of the injured tissue continues, fibroblasts and macrophages begin to remodel the area, degrading the proteins that form the provisional blood clot matrix and replacing them with a matrix that more resembles the normal, surrounding tissue. Fibroblasts secrete proteases, including matrix metalloproteinases, that digest the plasma fibronectin, and then the fibroblasts secrete cellular fibronectin and assemble it into an insoluble matrix. Fragmentation of fibronectin by proteases has been suggested to promote wound contraction, a critical step in wound healing.


Fibronectin is necessary for embryogenesis, and inactivating the gene for fibronectin results in early embryonic lethality. Fibronectin is important for guiding cell attachment and migration during embryonic development.


Fibronectin is also found in normal human saliva, which helps prevent colonization of the oral cavity and pharynx by potentially pathogenic bacteria.


Q. G proteins; structure, funtion, activation, examples of signaling through G proteins


Ans.


G proteins are so-called because they bind the guanine nucleotides GDP and GTP. They are heterotrimers (i.e., made of three different subunits) associated with


    * the inner surface of the plasma membrane and

    * transmembrane receptors of hormones, etc. These are called G protein-coupled receptors (GPCRs). 


The three subunits are:


    * G-alpha, which carries the binding site for the nucleotide. At least 20 different kinds of G-alpha molecules are found in mammalian cells.

    * G-beta

    * G-gamma 


How They Work


    * In the inactive state, G-alpha has GDP in its binding site.

    * When a hormone or other ligand binds to the associated GPCR, an allosteric change takes place in the receptor (that is, its tertiary structure changes).


FUNCTION:


G proteins are important signal transducing molecules in cells. In fact, diseases such as diabetes, blindness, allergies, depression, cardiovascular defects and certain forms of cancer, among other pathologies, are thought to arise due to derangement of G protein signaling.


The human genomes encodes roughly 350 G protein-coupled receptors, which detect hormones, growth factors and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions.


    * This triggers an allosteric change in G-alpha causing

    * GDP to leave and be replaced by GTP.

    * GTP activates G-alpha causing it to dissociate from G-beta-G-gamma (which remain linked as a dimer).

    * Activated G-alpha in turn activates an effector molecule.


      The effector molecule is adenylyl cyclase - an enzyme in the inner face of the plasma membrane which catalyzes the conversion of ATP into the "second messenger" cyclic AMP (cAMP).


Activated G-alpha is a GTPase so it quickly converts its GTP to GDP. This conversion, coupled with the return of the G-beta and G-gamma subunits, restores the G protein to its inactive state.


G protein can refer to two distinct families of proteins. Heterotrimeric G proteins, sometimes referred to as the "large" G proteins that are activated by G protein-coupled receptors and made up of alpha , beta , and gamma subunits. There are also "small" G proteins (20-25kDa) that belong to the Ras superfamily of small GTPases. These proteins are homologous to the alpha subunit found in heterotrimers, and are in fact monomeric. However, they also bind GTP and GDP and are involved in signal transduction.


Different types of heterotrimeric G proteins share a common mechanism. They are activated in response to a conformation change in the G-protein-coupled receptor, exchange GDP for GTP, and dissociate to activate other proteins in the signal transduction pathway. The specific mechanisms, however, differ among the types.


Activation


When a ligand activates the G protein-coupled receptor, it induces a conformational change in the receptor that allows the receptor to function as a guanine nucleotide exchange factor (GEF) that exchanges GDP for GTP on the G-alpha subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the Ga subunit, bound to GTP, from the G-beta-gamma dimer and the receptor. However, models that suggest molecular rearrangement, reorganization, and pre-complexing of effector molecules are beginning to be accepted. Both G-alpha GTP and G-beta-gamma can then activate different signaling cascades (or second messenger pathways) and effector proteins, while the receptor is able to activate the next G protein.

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