Lippincott's Biochemistry Chapter 21 - Amino Acids Conversion to Specialized Products PDF

Amino Acids: Conversion to Specialized Products I. OVERVIEW Dietary protein...

Amino Acids: Conversion to Specialized Products I. OVERVIEW Dietary protein 100 g.'day typical In addition to serving as building blocks for proteins, amino acids are of U.S. diet precursors of many nitrogen-containing compounds that have impor- tant physiologic functions (Fig. 21.1). These molecules include porphy- Synlheal8of non8H8ntlal rins, neurotransmitters, hormones, purines, and pyrimidines. [Note: See amlnoaclda p. 151 for 1he synthesis of nitric oxide from arginine.] varlea II. PORPHYRIN METABOLISM Porphyrins are cyclic compounds that readily bind metal ions, usually ferrous (Fe2 ) or ferric (Fe/ iron. The most f.revalent metalloporphyrin in humans is heme, which consists of one Fe + coordinated in 1he center of the tetrapyrrole ring of protoporphyrin IX {see p. 279). Heme is the prosthetic group for hemoglobin (Hb), myoglobin, 1he cytochromes, the SJnlh la ot: cytochrome P450 (CYP} monooxygenase system, catalase, nitric oxide Poqthwrfna synthase, and peroxidase. These hemeproteins are rapidly synthesized......... Creldlne and degraded. For example, 6-7 g of Hb is synthesized each day to replace heme lost through the normal turnover of erythrocytes. The syn- Var188........... tNlmnltten Prtlmleln.. thesis and degradation of the associated porphyrins and recycling of the iron are coordinated with the turnover of hemeproteins............ Otllernltroeen- eenllllnlng A. Structure Porphyrins are cyclic planar molecules formed by 1he linkage of four Glucoee, Ketone bodies, pyrrole rings 1hrough methenyl bridges (Fig. 21.2). Three structural glycogen faltyaclds features of these molecules are relevant 10 understanding their medi- cal significance. 1. Side chains: Different porphyrins vary in the nature of the side I carbon dioxide. water J chains attached to each of the four pyrrole rings. Uroporphyrin con- tains acetate (-CH2-COO-) and propionate (-CH~H~) Figure 21.1 side chains; coproporphyrin contains methyl (-CHa) and propionate Amino acids as precursors of groups; and protoporphyrin IX (and heme b, the most common heme) nitrogen-oontaining compounds. 2Tl 278 21. Amino Acids: Conversion to Specialized Products A and P are reveraed In rtng D of uroporphyrln Ill compared with uroporphyrln I. Only type p Porphyrlns contain Ide chalna Ill (asymmetric) porphyrlns attached to each of tlte 1our are phplologlcaJly Important pyrrole rings. In tvlM I In humans. porphyrtna, 1he aide chain are arranged aymmetrlcally, that la, for uroporphyrtn I, A (acelate) A attematea with P (propionate) around the tetrepyrrole ring. Uroporphyrln I Uroporphyrln Ill Flgure21.2 Structures of uroporphyrin I and uroporphyrin Ill. contains vinyl (-CH=CH2), methyl, and propionate groups. [Note: coo- l The methyl and vinyl groups are produced by decarboxylation of CfH2 acetate and propionate side chains, respectively.] 9~-coo- yH2 NH3+ O=C- CoA 2. Side chain distribution: The side chains of porphyrins can be Glycine Succlnyl CoA ordered around the tetrapyrrole nucleus in four different ways, des- l ) ignated by Roman numerals I to IV. Only type Ill porphyrins, which ALAS1 ~............ Herne contain an asymmetric substitution on ring D (see Fig. 21.2), are (mlll:lc:handrlal physiologically important in humans. [Note: Protoporphyrin IX is a enzyme) PLP '-+ CoA member of the type Ill series.] ' ~Ct 3. Porphyrlnogens: These porphyrin precursors (for example, uro- coo- l porphyrinogen) exist in a chemically reduced, colorless form and 9Ha serve as intermediates between porphobilinogen (PBG) and the 9~ oxidized, colored protoporphyrins in heme biosynthesis. C=O I 9~ B. Heme blosyn1hesla NH3+ The major sites of heme biosynthesis are the liver, which synthesizes 6-Amlnolevullnlc acid (ALA) = a number of heme proteins (particularly the CYP proteins), and the ~con':=)les erythrocyte-producing cells of the bone marrow, which are active in Hb synthesis. In the liver, the rate of heme synthesis is highly vari- (cytoaollc enzyme) 2 H~ able, responding to alterations in the cellular heme pool caused by Lead.............,,. 0 fluctuating demands for hemeproteins. In contrast, heme synthesis coo- l in erythroid cells is relatively constant and is matched to the rate of 900-91i2 globin synthesis. [Note: Over 85% of all heme synthesis occurs in 9~ 9H2 erythroid tissue. Mature red blood cells (RBC) lack mitochondria and c- c are unable to synthesize heme.] The initial reaction and the last three II II C, ,.-CH steps in the formation of porphyrins occur in mitochondria, whereas I~ y~ the intermediate steps of the biosynthetic pathway occur in the cyto- NH2 sol. [Note: Fig. 21.8 summarizes heme synthesis.) Porphoblllnogen 1. 6-Amlnolevullnlc acid formation: All the carbon and nitrogen atoms of the porphyrin molecule are provided by glycine {a nones- Figure21.3 sential amino acid) and succinyl coenzyme A {a tricarboxylic acid Pathway of porphyrin synthesis: cycle intermediate) that condense to form o-aminolevulinic acid Formation of porphobilinogen. (ALA) in a reaction catalyzed by ALA synthase ([ALAS], Fig. 21.3). [Note: Af.AS2 is regulated by iron.] This reaction requires pyridoxal phosphate ([PLP] see p. 382) as ALAS =6-aminolevulinic acid a coenzyme and is the committed and rate-limiting step in porphy- synthase; CoA =coenzyme A; CO:! = carbon dioxide; PLP ""' pyridoxal rin biosynthesis. [Note: There are two ALAS isoforms, each pro- phosphate. (Continued in Figs. 21.4 duced by different genes and controlled by different mechanisms. and 21.5.) ALAS1 is found in all tissues, whereas ALAS2 is erythroid specific. II. Porphyrin Metabolism 279 Loss-of-function mutations in ALAS2 result in X-linked sideroblas- Porphoblllnogen tic anemia and iron overload.] a. Heme (hemln) effects: When porphyrin production exceeds Hydlr»cymeltry· ~Four mo1acu1as bilane J'ltha condense) the availability of the apoproteins that require it, heme accumu- 4NHa lates and is converted to hemin by 1he oxidation of Fe2+ 10 Fe3+. Hemin decreases the amount (and, thus, 1he activity) of ALAS1 Hydroxymethylbllane by repressing transcription of its gene, increasing degradation of its messenger RNA, and decreasing import of 1he enzyme Umpotphyrlnogen 1111 (Ring closure and synflretl8 isomerization) into mitoohondria. [Note: In erythroid cells, ALAS2 is controlled by 1he availability of intracellular iron (see p. 475).) ~ CHz-cocr b. Drug effect8: Administration of any of a large number of drugs u CHz-CH2- 00CT results in a significant increase in hepatic ALAS1 actMty. These H drugs are metabolized by the microsomal CYP monooxygenase -ooc-c"2.....· ~ Q "": CH -coo- system, a hemeprotein oxk:/ass system found in the liver (see -ooc-cH2CH2 ~ 2 CH2-CH2 -cocr p. 149}. In response 10 these drugs, the synthesis of CYP proteins increases, leading to an enhanced consumption of heme, a com- Uroporphyrtnogen Ill ponent of these proteins. This, in turn, causes a decrease in the concentration of heme in liver cells. The lower intracellular heme UmpotplryrlnogtJ ~ Ill~(Oec:erboxyllltiOn) concentration leads to an increase in the synthesis of ALAS1 and 4C02 prompts a corresponding inct'9aS8 in the synthesis of ALA -OOC- CH2- C ~ ~ Cfis 2. Porphoblllnogan formation: The cytosolic condensation of two CHs ~ NH ~ u CHz-CH2- 00CT ALA to form PBG by zinc-containing ALA dshydratase (PBG syn- H thaS9) is extremely sensitive 10 inhibition by heavy metal ions (for Cfis f" "": Cfis example, lead) that replace the zinc (see Fig. 21.3). This inhibition -OOC-CH2-CH2 ° ~ CH2-CH2-COO- is, in part, responsible for the elevation in ALA and the anemia Coproporphyrtnogen Ill seen in lead poisoning. Copropolphyrtnogen Ill cWdlse (mltochondrtel ~Oecarboxylatton, :.....: ) 3. Uroporphyrlnogen formation: The condensa1ion of four PBG ~J ox......on 2~ produces the linear tetrapyrrole hydroxymethylbilane, which is CHz"'CH "": ~ CHa cyclized and isomerized by uroporphyrinogen Ill synthase to pro- CH3 ~ N N # CH=CH2 duce 1he asymmetric uroporphyrinogen Ill. This cyclic tetrapyrrole HH undergoes decarboxylation of its aceta1e groups by uropcrphyrino- H H gen Ill decarboxylsse (UROC1J, generating coproporphyrinogen Ill ~ CHs ~ (Fig. 21.4). The reactions occur in the cytosol. -OOC-CH2- CHz CH2-~-00CT Protoporphyrtnogen IX 4. Heme formation: Coproporphyrinogen Ill enters the mitochon- drion, and two propionate side chains are decarboxylated by coproporphyrinogen Ill oxidase to vinyl groups generating proto- ~.)llfttogen t (Oxidation) HzC=C "": Cfia porphyrinogen IX, which is oxidized to protoporphyrin IX. The intro- c~ ~ ~ ~ ~ CH=CHa duction of iron (as Fe21 into protoporphyrin IX produces heme. This step can occur spontaneously, but the rate is enhanced by HN ferrochelatass, an enzyme that, like ALA dehydratase, is inhibited # CHa CHz- CHz- OOCT by lead (Fig. 21.5). Protoporphyrtn IX C. Porphyrias Porphyrias are rare, inherited (or sometimes acquired) defects in heme Figure21.4 synthesis, resulting in the accumula1ion and increased excretion of por- Pathway of porphyrin synthesis: formation of protoporphyrin IX. phyrins or porphyrin precursors (see Fig. 21.8). [Note: Inherited por- (Continued from Fig. 21.3.) The phyrias are autosominal-dominant (AD) or autosomal-recessive (AR) prefixes -uro (urine} and -copro disorders.] Each porphyria resuHs in 1he accumulation of a unique pat- (feces) reflect initial sites of discovery. tern of intermediates caused by 1he deficiency of an enzyme in the [Note: Deficiency in uroporphyrinogen heme synthetic pathway. [Note: Porphyria, derived from the Greek for Ill synthase prevents isomerization, resulting in production of type I purple, refers to the red-blue color caused by pigment-like porphyrins in porphyrins.] the urine of some patients with defects in heme synthesis.] 280 21. Amino Acids: Conversion to Specialized Products 1. Cllnlcal manifestations: The porphyrias are classified as eryth- ropoietic or hepatic, depending on whether the enzyme deficiency occurs in the erythropoietic cells of the bone marrow or in the liver. Hepatic porphyrias can be further classified as chronic or acute. In general, individuals with an enzyme defect prior to the synthesis of the tetrapyrroles manifest abdominal and neuropsychiatric signs, whereas those with enzyme defects leading to the accumulation of tetrapyrrole intermediates show photosensitivity (that is, their ~~ 0 ~nmmm Leed (miloc:hondrial el,Zyme} HzC=CH ~ e Cfia 2 H+ skin itches and burns [pruritus] when exposed to sunlight). [Note: Photosensitivity is a result of the oxidation of colorless porphyrino- gens to colored porphyrins, which are photosensitizing molecules thought to participate in the formation of superoxide radicals from Cfia \. N "' \ N ~ CH=CH2 oxygen. These radicals can oxidatively damage membranes and r ):9 cause the release of destructive enzymes from lysosomes.] , ' N N CHa ~ # Cfia a. Chronic hepatic porphyrta: Porphyria cutanea tarda, the most -OOC- CH2- CH2 CH2 -CH2-ooo- common porphyria, is a chronic disease of the liver. The disease Hame (FeZ+ protoporphyrtn IX) is associated with severe deficiency of UROD, but