(BQ) Part 2 book The big picture: Medical biochemistry presents the following contents: Metabolism and vitamins mineras, the digestive system, muscles and motility, connective tissue and bone, blood, the immune system, the cardiovascular system, the respiratory system, the urinary system, the nervous system, the reproductive system,... Invite you to consult.
SECTION III APPLIED BIOCHEMISTRY CHAPTER 10 METABOLISM AND VITAMINS/MINERALS Co-authors/Editors: Maria L Valencik and Cynthia C Mastick Uni vers i ty of Neva da School of Medi ci ne, Depa rtment of Bi ochemi s try, Reno, NV Meta bol i c Rol es of Ma jor Bi ochemi ca l Mol ecul es Integra ti on a nd Regul a ti on of Meta bol i s m Hormona l Control of Meta bol i s m Vi ta mi ns a nd Mi nera l s Revi ew Ques ti ons OVERVIEW The i ntegra ti on of meta bol i s m i s a s tory of s uppl y a nd dema nd Food i s i nges ted to s uppl y energy but mus t be converted to the ca rbohydra te, l i pi d, a nd a mi no a ci d forms the body ca n us e, pri ma ri l y gl ucos e a nd fa tty a ci ds Indi vi dua l cel l s then convert the fuel s to us a bl e energy, a denos i ne tri phos pha te (ATP) a nd ni coti na mi de a deni ne di nucl eoti de (NADH) The body dema nds energy to functi on but i ndi vi dua l orga ns a nd ti s s ues requi re pa rti cul a r s ources of energy under va ryi ng condi ti ons To convert cons umed food i nto the needed energy, the body us es a va ri ety of orga ns , ea ch wi th uni que meta bol i c profi l es , to i ntegra te a nd regul a te the us e a nd s tora ge of energy Speci fi c regul a tory poi nts of bi ochemi ca l pa thwa ys provi de i mmedi a te control of the us a ge, convers i on, or s tora ge of food energy Va ri ous hormones ca n a l s o regul a te thes e bi ochemi ca l pa thwa ys to provi de l onger term control of food convers i on a nd energy us a ge Es s enti a l to both of thes e proces s es i s the ma i ntena nce of gl ucos e homeos ta s i s Fi na l l y, vi ta mi ns a nd mi nera l s s erve i mporta nt functi ons a s cofa ctors i n ma ny of thes e meta bol i c rea cti ons Thei r defi ci ency or exces s ca n l ea d to numerous di s ea s e s ta tes METABOLIC ROLES OF MAJOR BIOCHEMICAL MOLECULES The fi rs t cons i dera ti on i s the ma jor s ources of energy tha t ca n be us ed by the body, the nutri ents requi red for thei r meta bol i s m, a nd the bi ochemi ca l pa thwa ys tha t i ntegra te them Amino acids (Cha pter 1, Fi gure 10-1) provi de s evera l ma jor bi ochemi ca l functi ons , i ncl udi ng s ervi ng a s (1) the bui l di ng bl ocks of protei ns ; (2) the precurs ors of hormones , neurotra ns mi tters , a nd other i mporta nt s i gna l i ng mol ecul es (s uch a s ni trous oxi de); a nd (3) contri butors to the puri ne a nd pyri mi -di ne components of nucl ei c a ci ds , co-enzymes [NADH a nd fl a vi n a deni ne di nucl eoti de (FADH )], a nd other funda menta l bi ol ogi ca l mol ecul es Addi ti ona l l y, exces s a mi no a ci ds ca n enter the ci tri c a ci d cycl e a nd ca n be us ed to genera te or s tore bi ol ogi ca l energy (Cha pter 5) Furthermore, the meta bol i s m of s ome a mi no a ci ds ca n be funnel ed i nto gl ucos e s ynthes i s (gl uconeogenes i s ) duri ng food depri va ti on Figure 10-1 Summary of Amino Acid Metabolism [Reproduced wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.] Carbohydrates (Cha pter 2, Fi gure 10-2) perform a funda menta l rol e a s the pri ma ry energy-producti on s ource for the huma n body Gl ycol ys i s a nd the s ubs equent meta bol i c pa thwa ys form the pri ma ry energy mol ecul es ATP, NADH, a nd FADH vi a the oxi da ti on of gl ucos e a nd other ca rbohydra tes (Cha pter 6) Stora ge of ca rbohydra tes a s gl ycogen offers a rea di l y a va i l a bl e s ource of energy when di eta ry ca rbohydra te i nta ke i s l ow (Cha pter 2) Ca rbohydra tes a re a l s o i mporta nt i n the s ynthes i s of ni coti na mi de a deni ne di nucl eoti de phos pha te (NADPH) (Cha pter 6) a nd nucl ei c a ci ds (Cha pter 4) Figure 10-2 Transport and Fate of Major Carbohydrates and Amino Acids [Reproduced wi th permi s s i on from Murra y RA, et a l : Ha rper’s Il l us tra ted Bi ochemi s try, 28th edi ti on, McGra w-Hi l l , 2009.] Lipids (Cha pter 3, Fi gure 10-3) a re nonpol a r bi omol ecul es In mos t ti s s ues , they s erve a pri ma ry s tructura l rol e a s the components of bi ol ogi ca l membra nes , crea ti ng a l i pi d bi l a yer vi a thei r hydrophobi c a nd hydrophi l i c enti ti es (Cha pters a nd 8) Thei r rol es i n membra nes a s wel l a s i n pa thol ogi ca l proces s es s uch a s a theros cl eros i s (Cha pter 16) ve i s ed the a wa renes s of s a tura ted, mono-uns a tura ted, a nd pol yuns a tura ted forms wi th rega rd to thei r rol e i n di et However, i n a di pos e ti s s ue, tri gl yceri des a re the ma jor s tora ge form of bi ol ogi ca l energy a nd thei r oxi da ti on yi el ds more energy per ca rbon tha n ca rbohydra tes (Cha pter 7) Li pol ys i s of tri gl yceri des mobi l i zes fa tty a ci ds tha t genera te energy through β-oxi da ti on a nd produces the s ubs tra tes neces s a ry for ketone body (a cetoa ceta te a nd β-hydroxybutyra te) s ynthes i s , a n es s enti a l fuel s ource duri ng prol onged s ta rva ti on Oxi da ti on of both fa tty a ci ds a nd ketone bodi es s pa res gl ucos e by preventi ng i ts oxi da ti on The cons umpti on of di eta ry chol es terol a nd fa ts s a l a rge i mpa ct on l i pi d meta bol i s m through the genera ti on of pl a s ma l i poprotei ns [chyl omi crons a nd l ow-dens i ty l i poprotei n (LDL) vi a very-l ow-dens i ty l i poprotei n (VLDL)] The res ul ta nt el eva ti on of rmful l i pi ds /l i poprotei ns (dys l i pi demi a ) s nega ti ve meta bol i c cons equences tha t di rectl y i mpa ct hea l th a nd di s ea s e throughout a l l s oci oeconomi c cl a s s es of modern s oci ety Figure 10-3 Transport and Fate of Major Lipid Substrates and Metabolites FFA, free fa tty a ci ds ; LPL, l i poprotei n l i pa s e; MG, monoa cyl gl ycerol ; TG, tri a cyl gl ycerol ; a nd VLDL, very-l ow-dens i ty l i poprotei n [Reproduced wi th permi s s i on from Murra y RA, et a l : Ha rper’s Il l us tra ted Bi ochemi s try, 28th edi ti on, McGra w-Hi l l , 2009.] Vitamins, both l i pi d a nd nonl i pi d deri ved, s erve i mporta nt rol es a s cofa ctors i n meta bol i c pa thwa ys a nd rea cti ons (s ee end of thi s cha pter) Severa l di s ea s es , i ncl udi ng s curvy, ri ckets , a nd Werni cke–Kors a koff s yndrome, res ul t di rectl y from defi ci enci es of vi ta mi ns or, a s i n perni ci ous a nemi a , from the body’s i na bi l i ty to properl y a bs orb them Minerals, i ncl udi ng s odi um, pota s s i um, chl ori de, ca l ci um, phos pha te, i ron, a nd others , pl a y ma jor rol es i n the regul a ti on of meta bol i c enzymes i nvol ved i n di ges ti on, i n the us e a nd/or s tora ge of food meta bol i tes , a nd i n the el i mi na ti on of wa s te products Even more i mporta nt i s the i ntegra ti on of meta bol i s m of thes e mol ecul es i n the huma n body a nd how regul a ti on ca n be ma i nta i ned by i nterrel a ti ons hi ps between thei r a na bol i c a nd ca ta bol i c meta bol i s m In thi s rega rd, the body’s a bi l i ty to s ens e energy l evel s , res pond to hormone s i gna l i ng, a nd upregul a te a nd downregul a te pa rti cul a r meta bol i c pa thwa ys i s pa mount for the body to ma i nta i n the proper a nd control l ed l evel of meta bol i c functi on a nd for the myri a d of s tructura l a nd functi ona l proces s es to occur, whi ch a l l ow l i fe INTEGRATION AND REGULATION OF METABOLISM 2+ ATP, a s s oci a ted wi th ma gnes i um (Mg ) for s ta bi l i ty, i s the pri ma ry form of bi ol ogi ca l energy uti l i zed by the huma n body (Fi gure 10-4) Figure 10-4 Adenosine Triphosphate Structure with Its Magnesium Cofactor [Reproduced wi th permi s s i on from Murra y RA, et a l : Ha rper’s Il l us tra ted Bi ochemi s try, 28th edi ti on, McGra w-Hi l l , 2009.] As s uch, the ca ta bol i c oxi da ti on of ca rbohydra tes (gl ycol ys i s , ci tri c a ci d cycl e, a nd oxi da ti ve phos phoryl a ti on), fa tty a ci ds / l i pi ds /ketone bodi es (fa tty a ci d degra da ti on), a nd a mi no a ci ds a l l l ea d eventua l l y to the producti on of ATP In contra s t, a na bol i c meta bol i c proces s es (gl uconeogenes i s , gl ycogen s ynthes i s , l i pi d s ynthes i s , tri gl yceri de s ynthes i s , a nd a mi no a ci d s ynthes i s ) cons ume ATP, NADH, a nd/or NADPH to s tore energy (gl ucos e), to s tore energy, or to bui l d es s enti a l bi omol ecul es Coupl ed to a l l of thes e proces s es i s the need to el i mi na te wa s te products , i ncl udi ng CO2 (exha l a ti on, a ci d–ba s e ba l a nce), rea cti ve a nd/or free-ra di ca l s peci es (a nti oxi da nts ), a nd urea (urea cycl e) Thes e concepts a re s umma ri zed i n Fi gure 10-5 Figure 10-5 Interrelationship Between Proteins, Carbohydrates, and Fats ATP, a denos i ne tri phos pha te; CoA, coenzyme A [Ada pted wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.] Thes e meta bol i c pa thwa ys a re i nti ma tel y l i nked a t s evera l poi nts i n bi ochemi ca l pa thwa ys , but a re a l s o s epa ted i nto di s ti nct compa rtments a nd/or orga nel l es (e.g., cytopl a s m vers us mi tochondri a vers us nucl eus , etc.) to a l l ow the neces s a ry regul a ti on a nd control Addi ti ona l l y, ea ch orga n s uni que meta bol i c needs a nd functi ons a s s umma ri zed i n Fi gure 10-6 Thes e functi ons a nd needs mus t be coordi na ted i n a va ri ety of orga ns to ma i nta i n a cons ta nt s uppl y of energy whi l e pres ervi ng s ome energy for the future The body a ccompl i s hes thi s goa l by us i ng the nervous s ys tem a nd hormona l s i gna l s to di fferenti a l l y s ti mul a te a nd i nhi bi t bi ochemi ca l pa thwa ys wi thi n va ri ous orga ns i n res pons e to s uppl y a nd dema nd The ma i n s i gna l s us ed to regul a te meta bol i s m a re i ns ul i n, gl uca gon, ca techol a mi nes , gl ucocorti coi ds , a nd growth hormone (i n chi l dren) Figure 10-6 Integration of Metabolism Among Major Organs [Ada pted wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.] The rema i nder of thi s cha pter wi l l focus on the meta bol i s m i n three ma jor ti s s ues , the l i ver, a di pos e ti s s ue, a nd s kel eta l mus cl e (Fi gure 106) The l i ver a cti vel y provi des the qui ck fuel (gl ucos e) your body needs , wherea s a di pos e ti s s ue provi des l ong-term energy s tora ge Fi na l l y, s kel eta l mus cl e a nd the res t of your body cons ta ntl y dema nd thi s energy For exa mpl e, the bra i n cons umes a pproxi ma tel y 90 g of gl ucos e i n a da y, 20% of the a vera ge di et The s uppl y a nd dema nd of energy mus t be conti nuous l y provi ded vi a di eta ry i nta ke or brea kdown of s tores to ba l a nce wi th the energy requi rements of res pi ti on, tra ns port, moti l i ty, a nd s ynthes i s of cel l s a nd ti s s ues (Fi gure 10-7) Overa l l , the a vera ge a dul t us es a pproxi ma tel y 24 kca l of energy per ki l ogra m of body ma s s to i ns ure proper hea l th a nd to ma i nta i n proper wei ght Figure 10-7 Factors Affecting Blood Glucose [Reproduced wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.] Severa l key bi omol ecul es (gl ucos e-6-phos pha te or G6-P, pyruva te, a nd a cetyl coenzyme A or a cetyl -CoA) l i nk the bi ochemi ca l pa thwa ys for ca rbohydra tes , l i pi ds , a nd a mi no a ci ds / protei ns a nd the pa thwa ys they funnel i nto a re ti ghtl y regul a ted a nd ti s s ue s peci fi c (Fi gure 10-8) G6P, pyruva te, a nd a cetyl -CoA l i nk the a na bol i c a nd ca ta bol i c pa thwa ys of ca rbohydra te meta bol i s m to ma i nta i n a cons ta nt s uppl y of energy to ma i nta i n homeos ta s i s under cons ta ntl y cha ngi ng condi ti ons The pa rti cul a r pa thwa ys a nd regul a ti on a l s o depend on the s peci fi c functi ons a nd needs of ea ch ti s s ue type Figure 10-8 Summary of Important Control Points of Metabolism The three i mporta nt i ntermedi a ri es , gl ucos e-6-phos pha te, pyruva te, a nd a cetyl CoA a re i ndi ca ted Meta bol i c pa thwa ys of i mporta nce a re i ndi ca ted i n red See text for ful l di s cus s i on ATP, a denos i ne tri phos pha te; CoA, coenzyme A; NADPH, ni coti na mi de a deni ne di nucl eoti de phos pha te [Ada pted wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.] GLUCOSE-6-PHOSPHATE Meta bol i c regul a ti on a t thi s fi rs t bra nch poi nt, G6-P, i s cl ea rl y i l l us tra ted i n the l i ver (Fi gure 10-8) After the i nges ti on of ca rbohydra tes , gl ucos e ta ken up by the l i ver i s converted to G6-P by gl ucoki na s e Thi s phos phoryl a ti on us es one ATP mol ecul e a nd tra ps the gl ucos e wi thi n l i ver cel l s (hepa tocytes ) Subs equentl y, G6-P i s meta bol i zed vi a one of the fol l owi ng three pa thwa ys : (a ) glycogenesis—the s tora ge of ca rbohydra tes a s gl ycogen, (b) glycolysis—the producti on of ATP, or (c) the pentose phosphate pathway—the producti on of NADPH a nd/ or fi ve-ca rbon (pentos e) s uga rs (Cha pter 6, Fi gure 10-8) The pa thwa y chos en depends upon the a cti va ti on s ta te of key enzymes (glycogen synthase a nd phosphofructokinase-1), s ubs tra te a va i l a bi l i ty (G6-P, ATP, a nd NADP+), a nd a l l os teri c effectors [ATP, a denos i ne monophos pha te (AMP), fructos e 2,6-bi s phos pha te (F2,6BP), hydrogen i ons (H +), a nd ci tra te] The key enzymes i n gl ycogenes i s a nd gl ycol ys i s a re predomi na ntl y regul a ted by hormone-s ti mul a ted, cova l ent modi fi ca ti on (phosphorylation), wherea s the a l l os teri c effectors fi ne-tune the fl ow of ca rbons through thes e pa thwa ys In contra s t, the pentos e phos pha te pa thwa y i s pri ma ri l y regul a ted by the a va i l a bi l i ty of G6-P a nd NADP+ (Cha pter 6) In the wel l -fed s ta te, when ATP a nd ci tra te concentra ti ons a re hi gh, phosphofructokinase-1 i s a l l os teri ca l l y i nhi bi ted, s l owi ng down the commi tted s tep of gl ycol ys i s (the producti on of fructose 1,6-bisphosphate) l ea di ng to i ncrea s ed concentra ti ons of G6-P The i ncrea s ed concentra ti on of G6-P ca n s ti mul a te ca rbohydra te s tora ge i n two wa ys Fi rs t, G6-P i s a pos i ti ve a l l os teri c effector of glycogen synthase, l ea di ng to the forma ti on of gl ycogen Second, G6-P i ndi rectl y i nhi bi ts glycogen phosphorylase thereby i nhi bi ti ng glycogenolysis (gl ycogen degra da ti on) Al terna ti vel y, when the ti o of NADP+ to NADPH i s hi gh, G6-P ca n be s huttl ed i nto the pentos e phos pha te pa thwa y to genera te NADPH (reducti ve energy) Thi s reduci ng power i s us ed to s ynthes i ze a va ri ety of bi omol ecul es s uch a s , fa tty a ci ds , chol es terol , nucl eoti des a nd other cofa ctors a s needed Under condi ti ons where the ti o of NADP+ to NADPH i s l ow, the pentos e pa thwa y wi l l not opera te rega rdl es s of the concentra ti on of G6-P The producti on of gl ycogen i n the l i ver i s further control l ed by the hormones , i ns ul i n a nd gl uca gon (s ee bel ow), a nd the res ul ti ng phos phoryl a ti on or dephos phoryl a ti on of gl ycogen s yntha s e Degra da ti on of gl ycogen i s decrea s ed concomi ta ntl y by counterregul a tory dephos phoryl a ti on or phos phoryl a ti on of gl ycogen phos phoryl a s e Ea ti ng brea kfa s t, a fter a n overni ght fa s t, s ti mul a tes gl ycogen s ynthes i s (a nd i nhi bi ts gl ycogen brea kdown) i n prepa ti on for the next peri od of fa s ti ng Thi s repl eni s hment i s control l ed by the fa vora bl e hi gh ti o of i ns ul i n to gl uca gon, l ea di ng to a cti va ti on of gl ycogen s yntha s e a cti vi ty a nd decrea s ed gl ycogen phos phoryl a s e a cti vi ty Under thes e condi ti ons , the dema nd for de novo s ynthes i s of l i pi d wi l l ri s e a fter the gl ycogen i s repl a ced, us i ng ca rbons from exces s di eta ry ca rbohydra te (to s ynthes i ze fa tty a ci ds ) Addi ti ona l l y, i f chol es terol bi os ynthes i s i s a cti ve, exces s a cetyl Co A from fa tty a ci d ca ta bol i s m ca n be s ynthes i zed i nto chol es terol Once l i pi d bi os ynthes i s commences , the uti l i za ti on of NADPH i ncrea s es the NADP+/NADPH ti o fa vori ng fl ux through the pentos e phos pha te pa thwa y After a mea l , the key regul a tor tha t res ta rts gl ycol ys i s i n l i ver i s F2,6BP F2,6BP concentra ti on i s control l ed by a bifunctional enzyme tha t i ncl udes both ki na s e a nd phos pha ta s e a cti ve s i tes Under condi ti ons of a hi gh ti o of i ns ul i n to gl uca gon, the bi functi ona l enzyme (phosphofructokinase-2/fructose 2,6-bisphosphatase) i s dephos phoryl a ted, l ea di ng to s ti mul a ti on of phos phofructoki na s e-2 The res ul ti ng F2,6BP formed a l l os teri ca l l y a cti va tes phos phofructoki na s e-1 a nd hence i ncrea s es gl ycol ys i s whi l e s i mul ta neous l y i nhi bi ti ng fructos e 1,6 bi s phos pha ta s e, therefore s hutti ng down gl uconeogenes i s Fol l owi ng food depri va ti on, thes e events a re revers ed wi th a hi gh ti o of gl uca gon to i ns ul i n, fa vori ng phos phoryl a ti on of the bi functi ona l enzyme s ti mul a ti ng the fructos e 2,6-bi s phos pha ta s e a cti vi ty a nd l ea di ng to decrea s ed phos phofructoki na s e-1 a cti vi ty PYRUVATE The s econd ma jor bra nch poi nt i n the i ntegra ti on of meta bol i s m i s a t pyruvate (Cha pter 6, Fi gure 10-8) Pyruva te ca n be converted i nto four di fferent s ubs tra tes : l a cta te, a l a ni ne, oxa l o-a ceta te, a nd a cetyl -CoA, dependi ng upon the energy needs of a cel l Therefore, i t i s a n i mporta nt i ntegra ti on poi nt where ca rbons a re s huttl ed between energy s tora ge, energy genera ti on, a nd/or bi os yntheti c rea cti ons In the l i ver, pyruva te ca n undergo oxi da ti ve deca rboxyl a ti on to enter the ci tri c a ci d cycl e a nd ul ti ma tel y genera te ATP when energy l evel s a re l ow Speci fi ca l l y, l ow energy l evel s i nhi bi t the a cti vi ty of a n i mporta nt regul a tory enzyme, pyruvate dehydrogenase kinase Thi s i nhi bi ti on prevents phos phoryl a ti on of the pyruva te dehydrogena s e compl ex to a n i na cti ve s ta te Furthermore, thi s ki na s e i s i nhi bi ted by NAD +, pyruva te, a nd s ul fhydryl form of CoA (non-a cetyl a ted), s ubs tra tes of pyruva te dehydrogena s e Therefore, when s ubs tra tes a re pl enti ful , pyruva te i s oxi da ti vel y deca rboxyl a ted to a cetyl -CoA In the l i ver, pyruva te i s a l s o the poi nt where l a cta te a nd a l a ni ne (s ee bel ow) ca n be a cti vel y funnel ed i nto ei ther the ci tri c a ci d cycl e or gl uconeogenes i s vi a pyruva te ca rboxyl a ti on to oxa l oa ceti c a ci d (Cha pter 6) when l i ver gl ycogen or bl ood gl ucos e l evel s a re l ow Duri ng s ta rva ti on, gl uconeogenes i s ca n produce up to 160 g of gl ucos e i n a da y, l f of thi s from a mi no a ci ds Ha l f of thi s gl ucos e wi l l be us ed by the bra i n As bl ood gl ucos e l evel s s ta bi l i ze a nd gl uconeogenes i s i s no l onger requi red, oxa l oa ceta te ca n re-enter the gl ycol yti c pa thwa y a t phos phoenol pyruva te or s huttl e ba ck i nto the mi tochondri a , a s ma l a te, to be us ed i n the ci tri c a ci d cycl e If energy i s a bunda nt, hi gh NADH a nd a cetyl -CoA concentra ti ons a cti va te pyruva te dehydrogena s e ki na s e a nd a l s o s erve a s a l l os teri c i nhi bi tors of enzyma ti c a cti vi ti es wi thi n the PDH compl ex Thi s effecti vel y turns off the pyruva te dehydrogena s e compl ex by phos phoryl a ti on a nd a l l os teri c control a nd s huts down the ci tri c a ci d cycl e Hi gh ATP a nd a cetyl -CoA concentra ti ons a l s o s ti mul a te pyruvate carboxylase, the fi rs t s tep of gl uconeogenes i s (hormone regul a ti on of gl uconeogenes i s i s even more i mporta nt; s ee bel ow) Skel eta l mus cl e i l l us tra tes a nother i mporta nt wa y tha t pyruva te ca n be meta bol i zed (Fi gure 10-9) If oxygen l evel s a re l ow a nd anaerobic respiration becomes i mporta nt (s uch a s duri ng a qui ck s pri nt), pyruva te ca n be converted to lactate by lactate dehydrogenase wi th a n oxi da ti on of one NADH to NAD +, the l a tter bei ng es s enti a l for s us ta i ni ng gl ycol ys i s In thi s s cena ri o, ATP i s s ol el y deri ved from a na erobi c gl ycol ys i s La cta te ca n s ubs equentl y be converted ba ck to gl ucos e for energy producti on vi a the Cori cycle (i n the l i ver); when l a cta te concentra ti ons get too hi gh, feedba ck i nhi bi ti on bl ocks further convers i on of pyruva te to l a cta te Hi gh l a cta te concentra ti ons a l s o crea te the s ens a ti on of “burni ng” i n mus cl es , whi ch s erves a s a s i gna l to the body to l i mi t further us e of thes e mus cl es Furthermore, pyruva te ca n a l s o be converted i n mus cl e ti s s ue to the a mi no a ci d alanine vi a the alanine transaminase rea cti on In a ma nner a na l ogous to the Cori cycl e, the alanine cycle then converts thi s a l a ni ne ba ck to pyruva te i n the l i ver where i t i s us ed to produce new gl ucos e vi a gl uconeogenes i s a s a s ource of energy for a na erobi c gl ycol ys i s i n mus cl e Once oxygen l evel s a re res tored i n s kel eta l mus cl e, producti on of ATP vi a ci tri c a ci d cycl e/oxi da ti ve phos phoryl a ti on res umes Figure 10-9 The Lactic Acid (Cori) and Glucose–Alanine Cycles Ca rbons from gl ucos e meta bol i s m i n mus cl e a re recycl ed to the l i ver ei ther a s l a cta te or a l a ni ne for reconvers i on to gl ucos e Hence, when thes e cycl es opera te gl ucos e ca rbons a re s pa red [Ada pted wi th permi s s i on from Murra y RA, et a l : Ha rper’s Il l us tra ted Bi ochemi s try, 28th edi ti on, McGra w-Hi l l , 2009.] ACETYL-COA Acetyl-CoA i s the thi rd bra nch poi nt of pri ma ry meta bol i c control , a nd coordi na tes ca rbohydra te, ketone, a nd fa t/l i pi d pa thwa ys (Cha pter 6, Fi gures 10-8 a nd 10-10) Acetyl -CoA i s a s ubs tra te for the ci tri c a ci d cycl e a nd ca n be oxi di zed to genera te energy However, when energy l evel s a re hi gh (hi gh NADH/ NAD + ti o), NADH i nhi bi ts the ci tri c a ci d cycl e a t the i s oci tra te dehydrogena s e a nd α-ketogl uta te dehydrogena s e s teps Accumul a ti on of FADH a l s o occurs , l ea di ng to a n i ncrea s e i n s ucci nyl -CoA tha t i nhi bi ts the cycl e a s wel l Hormones a l s o pl a y a key, l onger term rol e i n the regul a ti on of fa tty a ci d s ynthes i s a nd degra da ti on (s ee bel ow) Acetyl -CoA i s a l s o requi red for producti on of the neurotra ns mi tter a cetyl chol i ne (s ee bel ow a nd Cha pter 19) Figure 10-10 Overview of Acetyl-CoA Metabolism ATP, a denos i ne tri phos pha te; CoA, coenzyme A; TCA, tri ca rboxyl i c a ci d [Ada pted wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.] In the fed s ta te, exces s a cetyl -CoA ca n be di rected towa rd s ynthes i s of chol es terol a nd/or fa ts /tri a cyl gl ycerol s i n the l i ver Duri ng s ta rva ti on, fa tty a ci d oxi da ti on s uppl i es energy for hepa tocytes to dri ve gl uconeogenes i s Furthermore, a ny exces s a cetyl -CoA genera ted wi l l be us ed for the s ynthes i s of ketone bodi es The ketones ca nnot be oxi di zed by the l i ver a nd a re exported a nd us ed a s a n a l terna te fuel for the bra i n, hea rt, a nd mus cl es In fa ct, duri ng fa s ti ng/s ta rva ti on, the bra i n wi l l be hea vi l y rel i a nt on ketone bodi es , us i ng them for up to 70% of i ts energy requi rements , es peci a l l y i n prol onged s ta rva ti on Hormones a l s o regul a te ketone body s ynthes i s (s ee bel ow) In both nutri ti ona l ci rcums ta nces , a cetyl -CoA ma y a cti va te pyruvate carboxylase, a l though for di fferent purpos es In the fed s ta te, pyruva te ca rboxyl a s e converts pyruva te to oxa l oa ce-ta te, whi ch condens es wi th a cetyl -CoA produci ng ci tra te, the fi rs t product of the ci tri c a ci d cycl e The ci tra te i s tra ns ported to the cytopl a s m for fa tty a ci d s ynthes i s Hi gh ci tra te a cti va tes acetyl-CoA carboxylase to promote the forma ti on of fa tty a ci ds (Cha pter 7) Ci tra te, when too hi gh, i nhi bi ts phos phofructoki na s e-1, thus bl ocki ng gl ycol ys i s to prevent unneces s a ry meta bol i s m of more gl ucos e to pyruva te The G6-P tha t ba cks up ca n be cycl ed through the pentos e pa thwa y to provi de NADPH for fa tty a ci d s ynthes i s , a s des cri bed a bove, or ma y be di rected towa rd gl ycogen s ynthes i s In the s ta rva ti on s ta te, hi gh a cetyl -CoA from oxi da ti on of fa tty a ci ds s ti mul a tes pyruva te ca rboxyl a s e to promote gl uconeogenes i s Low concentra ti ons of citrate a nd the other i ntermedi a tes of the ci tri c a ci d cycl e a s wel l a s l ow ATP/NADH/FADH promote conti nua ti on of the ci tri c a ci d cycl e a nd oxi da ti ve phos phoryl a ti on The ci tri c a ci d cycl e i ntermedi a tes ca n a l s o be us ed for the producti on of a mi no a ci ds or a s a n energy s ource (Cha pter 5) Low ci tra te/hi gh pa l mi toyl -CoA (from l i pol ys i s ) concentra ti ons prevent fa tty a ci d s ynthes i s The res ul ta nt decrea s e of malonyl-CoA, a n a l l os teri c i nhi bi tor of ca rni ti ne pa l mi toyl tra ns fera s e (CPT1), fa vors forma ti on of pa l mi toyl ca rni ti ne by CPT1, wi th s ubs equent tra ns port a cros s the mi tochondri a l membra ne a nd oxi da ti on i n the mi tochondri a HORMONAL CONTROL OF METABOLISM The coordi na ti on of meta bol i c pa thwa ys to a chi eve thi s es s enti a l ba l a nce pri ma ri l y depends on hormone; nerve a nd s i gna l i ng pa thwa ys , i ncl udi ng i ns ul i n, gl uca gon, ca techol a mi nes (Cha pter 19), gl ucocorti coi ds (s l ower, s tres s -rel a ted cha nges ); a nd cytoki nes Erra nt control l ea ds to di s ea s e s ta tes i f gl ucos e l evel s a re hi gh (di a betes mel l i tus or DM) or l ow (hypogl ycemi a ) a nd, i f too l ow, even dea th due to coma INSULIN Ins ul i n (Fi gure 10-11) i s the a na bol i c hormone of the wel l -fed s ta te a nd a n i mporta nt s i gna l to s ti mul a te s tora ge of exces s nutri ents a s gl ycogen a nd tri gl yceri des (fa t i n a di pos e ti s s ue) Figure 10-11 Preproinsulin Processing Preproi ns ul i n (top) i s compos ed of a l ea der s equence (bl ue), A (green) a nd B (yel l ow) i ns ul i n cha i ns , a nd C (red) pepti de Remova l of the l ea der s equence produces proi ns ul i n (bottom l eft) Cl ea va ge of C-pepti de from proi ns ul i n l ea ds to the producti on of a cti ve i ns ul i n Beca us e C-pepti de i s produced i n equa l a mounts to i ns ul i n, i t s become a n i mporta nt mea s ure of i ns ul i n producti on [Ada pted wi th permi s s i on from Ki bbl e JD a nd Ha l s ey CR: The Bi g Pi cture: Medi ca l Phys i ol ogy, 1s t edi ti on, McGra w-Hi l l , 2009.] The a cti on of i ns ul i n (Fi gure 10-12) i s experi enced by three ma i n ta rgets , the l i ver, a di pos e ti s s ue, a nd s tri a ted mus cl e The s ynthes i s a nd rel ea s e of i ns ul i n i s s ti mul a ted by gl ucos e a nd potenti a ted by a mi no a ci ds In the l i ver, i ns ul i n s ti mul a tes gl ycogenes i s (gl ycogen s ynthes i s ), fa tty a ci d s ynthes i s , gl ycol ys i s , a nd the pentos e phos pha te pa thwa y In the a di pos e ti s s ue, i t s ti mul a tes gl ucos e a nd fa tty a ci d upta ke a nd tri gl yceri de s ynthes i s (energy s tora ge) Si mi l a rl y, i n s kel eta l mus cl e, i t s ti mul a tes gl ucos e upta ke, gl ycogenes i s , a nd protei n s ynthes i s It i s noteworthy tha t i ns ul i n does not i nfl uence gl ucos e meta bol i s m i n ei ther the bra i n or red bl ood cel l s Figure 10-12 Metabolic Systems Affected by Insulin [Ada pted wi th permi s s i on from Na i k P: Bi ochemi s try, 3rd edi ti on, Ja ypee Brothers Medi ca l Publ i s hers (P) Ltd., 2009.] The rel ea s e of i ns ul i n from the pa ncrea ti c β-cel l s (Fi gure 10-13) i s the res ul t of i ncrea s ed bl ood gl ucos e concentra ti ons Gl ucos e enters the β-cel l s vi a the gl ucos e tra ns porter (GLUT2) (pa s s i ve tra ns port) The GLUT2 s a wea k a ffi ni ty for gl ucos e s o tha t i t fa vors gl ucos e upta ke onl y a fter a mea l , when bl ood gl ucos e l evel s a re hi gh, ther tha n i n the fa s ted s ta te Fol l owi ng gl ucos e oxi da ti on, the i ncrea s ed ATP concentra ti on s ti mul a tes K+ cha nnel s a nd depol a ri zes the cel l membra ne Thi s depol a ri za ti on opens vol ta ge-ga ted Ca 2+ cha nnel s Other s i gna l s rel a ted to producti on of i nos i tol tri s phos pha te, a s econd mes s enger, s ti mul a te Ca 2+ rel ea s e from the endopl a s mi c reti cul um, res ul ti ng i n hi gh i ntercel l ul a r Ca 2+ concentra ti on a nd tri ggeri ng the rel ea s e of i ns ul i n Figure 10-13 Regulation of Secretion of Insulin via Glucose Pa ncrea ti c β-cel l s a re i nduced to s ecrete i ns ul i n by (1) the upta ke of gl ucos e a nd i ts oxi da ti ve meta bol i s m i n mi tochondri a , whi ch produces i ncrea s ed concentra ti on of ATP (2) Increa s ed ATP ca us es cl os ure of the ATP-s ens i ti ve K+ cha nnel s , l ea di ng to depol a ri za ti on (3) The depol a ri za ti on of the cel l ca us es i n i nfl ux of Ca 2+ from vol ta ge-ga ted Ca 2+ cha nnel s (4) The i ncrea s ed Ca 2+ a l ong wi th IP3 a nd other s i gna l i ng i nduces further rel ea s e of Ca 2+ from the endopl a s mi c reti cul um (ER), whi ch prompts exocytos i s of i ns ul i n, produced i n the ER, a nd s ubs equentl y proces s ed a nd rel ea s ed from s ecretory gra nul es of the Gol gi a ppa tus ATP, a denos i ne tri phos pha te; GLUT2, gl ucos e tra ns porter 2; IP3 , i nos i tol tri s phos pha te [Ada pted wi th permi s s i on from Ki bbl e JD a nd Ha l s ey CR: The Bi g Pi cture: Medi ca l Phys i ol ogy, 1s t edi ti on, McGra w-Hi l l , 2009.] Ins ul i n a ffects the meta bol i s m of cel l s tha t ve i ns ul i n receptors : l i ver cel l s (hepa tocytes ), fa t cel l s (a di pocytes ), a nd mus cl e cel l s (Ta bl e 10-1) The bra i n a nd red bl ood cel l s a re not a ffected by i ns ul i n Ins ul i n works vi a a tyros i ne ki na s e receptor, whi ch phos phoryl a tes ta rget protei ns tha t l ea d to a number of meta bol i c effects One effect i s the pi d tra ns l oca ti on of a gl ucos e tra ns porter 4, GLUT4, from ves i cl es to the cel l s urfa ce of s kel eta l a nd ca rdi a c mus cl e a nd fa t cel l s , i ncrea s i ng gl ucos e tra ns port i nto thes e cel l s Ins ul i n a l s o regul a tes meta bol i c ... ri za ti on (3) The depol a ri za ti on of the cel l ca us es i n i nfl ux of Ca 2+ from vol ta ge-ga ted Ca 2+ cha nnel s (4) The i ncrea s ed Ca 2+ a l ong wi th IP3 a nd other s i gna l i... McGra w-Hi l l , 20 09 The a cti ons of ea ch of the a bove cel l types a nd, therefore, the envi ronment of the s toma ch a re control l ed by va gus nerve s i gna l s a s wel l a s the hormones... by the Digestive System Si tes of producti on of the fi ve ma jor ga s troi ntes ti na l hormones a l ong the l ength of the ga s troi ntes ti na l tra ct The wi dth of the ba rs i ndi ca tes the