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Just as humans employ tools toenhance and extend the capabilities of their hands, proteins often use smallnonprotein molecules to perform functions that would be difficult or impossible to do with amino acids alone. Thus, the signal receptor protein rhodopsin,which is made by the photoreceptor cells in the retina, detects light by means ofa small molecule, retinal, embedded in the protein (Figure 3-53A). Retinalchanges its shape when it absorbs a photon of light, and this change causestheprotein to trigger a cascade of enzymatic reactions that eventually lead to anelectrical signal being carried to the brain.Another example of a protein that contains a nonprotein portion ishemoglobin (see Figure 3-22).
A molecule of hemoglobin carries four hemegroups, ring-shaped molecules each with a single central iron atom (Figure3-538). Heme gives hemoglobin (and blood) its red color. By binding reversiblyto oxygen gas through its iron atom, heme enables hemoglobin to pick up oxygen in the lungs and releaseit in the tissues.sometimes these small molecules are attached covalently and permanentlyto their protein, thereby becoming an integral part of the protein molecule itself.we shall see in chapter l0 that proteins are often anchored to cell membranesthrough covalently attached lipid molecules.
And membrane proteins exposedCOOHIfn,9HzCOOHIT",CHzua-e,u, l La - uaH-HCH:CH:(A)(B)HCCHzFigure3-53 Retinaland heme.(A)Thestructureof retinal,the light-sensitivemoleculeattachedto rhodopsinin theeye.(B)The structureof a hemegroup.Thecarbon-containinghemering is redand the iron atom at its centeris orange.A hemegroup is tightlyboundto eachofthe four polypeptidechainsinhemoglobin,the oxygen-carryingproteinwhosestructureis shownin Fiqure3-22.167PROTEINFUNCTIONTable3-2 ManyVitaminsProvideCriticalCoenzymesfor HumanCellsT h i a m i n e( v i t a m i nB r )Riboflavin(vitaminBz)NiacinPantothenicacidPyridoxineBiotinLipoicacidFolicacidV i t a m i nB r zthiaminepyrophosphateFADHNADH,NADPHcoenzymeApyridoxalphosphatebiotinlipoamidetetrahydrofolatecobalamincoenzymesactivationand transferof aldehydesoxidation-reductionoxidation-reductionacyl group activationand transferamino acid activation;alsoglycogenphosphorylaseCO2activationand transferacyl group activation;oxidation-reductionactivationand transferof singlecarbon groupsisomerizationand methyl group transferson the surface of the cell, as well as proteins secreted outside the cell, are oftenmodified by the covalent addition of sugars and oligosaccharides.Enzymes frequently have a small molecule or metal atom tightly associatedwith their active site that assistswith their catalytic function.
Carboxypeptidase,for example, an enzyrne that cuts polypeptide chains, carries a tightly boundzinc ion in its active site. During the cleavageof a peptide bond by carboxypeptidase, the zinc ion forms a transient bond with one of the substrate atoms,thereby assisting the hydrolysis reaction. In other enzymes, a small organicmolecule servesa similar purpose. Such organic molecules are often referred toas coenzymes. An example is biotin, which is found in enzymes that transfer acarboxylate group (-COO-) from one molecule to another (see Figure 2-63).Biotin participates in these reactions by forming a transient covalent bond to the-COO- group to be transferred, being better suited to this function than any ofthe amino acids used to make proteins.
Because it cannot be synthesized byhumans, and must therefore be supplied in small quantities in our diet, biotin isa uitamin. Many other coenzymes are produced from vitamins (Table3-2). Vitamins are also needed to make other types of small molecules that are essentialcomponents of our proteins; vitamin A, for example, is needed in the diet tomake retinal, the light-sensitive part of rhodopsin.with MultipleMolecularTunnelsChannelSubstratesin EnzymesCatalyticSitesSome of the chemical reactions catalyzedby enzymes in cells produce intermediates that are either very unstable or that could readily diffuse out of the cellthrough the plasma membrane if released into the cltosol. To preserve theseintermediates, enzymes have evolved molecular tunnels that connect tvvo ormore active sites, allowing the intermediate to be rapidly processed to a finalproduct-withoutever leaving the enzyme.Consider, for example, the enzyme carbamoyl phosphate synthetase,whichuses ammonia derived from glutamine plus two molecules of ATP to convertbicarbonate (HCO3-) to carbamoyl phosphate-an important intermediate inseveral metabolic pathways (Figure 3-54).
This enzyme contains three widelyseparated active sites that are connected to each other by a tunnel. The reactionstarts at active site 2, located in the middle of the tunnel, where AIP is used tophosphorylate (add a phosphate group to) bicarbonate, forming carbory phosphate.
This event triggers the hydrolysis of glutamine to glutamic acid at activesite 1, releasing ammonia into the tunnel. The ammonia immediately diffusesthrough the first half of the tunnel to active site 2, where it reacts with the carboxyphosphate to form carbamate. This unstable intermediate then diffusesthrough the second half of the tunnel to active site 3, where it is phosphorylatedbyATP to the final product, carbamoyl phosphate.168Chapter3: ProteinsFigure3-54 The tunnelingof reactionintermediatesin theenzyme carbamoylphosphatesynthetase.(A)Diagramofthestructureof the enzyme,in whicha redribbonhasbeenusedtooutlinethe tunnelon the insideof the proteinconnectingits threeactivesites.Thesmalland largesubunitsof this dimericenzyme(B)The path of theare color codedyellow and blue,respectively.reaction.As indicated,activesite 1 producesammonia,whichdiffusesthroughthe tunnelto activesite2, whereit combineswith carboxyphosphateto form carbamate.Thishighlyunstableintermediatethen diffusesthroughthe tunnelto activesite3,whereit is phosphorylatedby ATPto producethe finalproduct,(A,modifiedfrom F.M.Raushel,carbamoylphosphate.J.B.Thoden,and H.M.Holden,Acc.Chem.Res.36:539-548,2003.Witnpermissionfrom AmericanChemicalSocietv.)IL]'l]]::]:,.']':]i]]'::]'.':l:','.|.i':.:],:].ooHzoIiltl- o/ /bicarbonateCP\q- llu t a m i n el\odo-p,' *lL+Iq l u t a m i ca c i dVNHrcarboxyphosphateIItNHjdiffusionII-",1.(B)Severalother well characterized enzymes contain similar molecular tunnels.Ammonia, a readily diffusable intermediate that might otherwise be lost fromthe cell, is the substrate most frequently channeled in the examples thus farkno'nrm.MultienzymeComplexesHelpto Increasethe Rateof CellMetabolismThe efficiency of enzymes in accelerating chemical reactions is crucial to themaintenance of life.
cells, in effect, must race against the unavoidable processes of decay, which-if left unattended-cause macromolecules to rundownhill toward greater and greater disorder. If the rates of desirable reactionswere not greater than the rates of competing side reactions, a cell would soondie. we can get some idea of the rate at which cell metabolism proceeds bymeasuring the rate of ArP utilization. A typical mammalian cell "turns over"(i.e.,hydrolyzes and restoresby phosphorylation) its entire ATp pool once everyI or 2 minutes.
For each cell, this turnover represents the utilization of roughly107molecules of AIP per second (or, for the human body, about I gram of nfi,everv minute).169PROTEINFUNCTIONThe rates of reactions in cells are rapid because enzyme catalysisis so effective. Many important enzymes have become so efficient that there is no possibility of further useful improvement.
The factor that limits the reaction rate is noIonger the enzyme's intrinsic speed of action; rather, it is the frequency withwhich the enzyme collides with its substrate. Such a reaction is said to be diffusion-limited (seePanel3-3, p. 162-163).If an enzyme-catalyzed reaction is diffusion-limited, its rate depends onthe concentration of both the enzyme and its substrate. If a sequence of reactions is to occur extremely rapidly, each metabolic intermediate and enzymeinvolved must be present in high concentration. However, given the enormousnumber of different reactions performed by a cell, there are limits to the concentrations that can be achieved. In fact, most metabolites are present inmicromolar (10-6 M) concentrations, and most enzyme concentrations aremuch lower.
How is it possible, therefore, to maintain very fast metabolic rates?The answer lies in the spatial organization of cell components. The cell canincrease reaction rates without raising substrate concentrations by bringing thevarious enzJ,.rnesinvolved in a reaction sequence together to form a large protein assembly knor.vn as a multienzyme complex (Figure 3-55).
Because thisA to be passeddirectly to enzyme B, and so on, difallows the product of enzJ,rynefusion rates need not be limiting, even when the concentrations of the substrates in the cell as a whole are very low. It is perhaps not surprising, therefore,that such enzyme complexes are very common, and they are involved in nearlyall aspects of metabolism-including the central genetic processes of DNA,RNA, and protein slmthesis.In fact, few enzymes in eucaryotic cells diffuse freelyin solution; instead, most seem to have evolved binding sites that concentratethem with other proteins of related function in particular regions of the cell,thereby increasing the rate and efficiency ofthe reactions that they catalyze.Eucaryotic cells have yet another way of increasing the rate of metabolicreactions: using their intracellular membrane systems.These membranes cansegregateparticular substratesand the enzymes that act on them into the samemembrane-enclosed compartment, such as the endoplasmic reticulum or thecell nucleus.
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