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892 Part VI: The Erythrocyte Chapter 58: The Porphyrias 893

Succinyl-CoA O OH a p
O OH
O OH O OH C
C CoA C C CH 2 B
2
Co 2 2, H O 4, NH 3 p N
H C CH 2 CH 2 CH 2 H a
2
H C ALAS (1) CH 2 ALAD (2) C C A NH HN C
2
C C O C CH PBGD (3) a
CoA O CH 2 H C N H p
N
H N 2 H HO D
HO C CH NH 2 2
ALA NH 2
O H PBG p a
Glycine
HMB
O
H 2
UROS (4)
a p
v
m
B
p N
B H a
N A NH HN C
m a
A N Fe N C H N p
m D
N p
D UROD (5) a p
Copro’gen III
m p m p
Uro’gen III
Heme B 4, CO 2
p N
H m
FECH (8) A NH HN C
Fe 2+ m H N p
v v D
m CPO (6)
m
B B m p
N 2, CO 2
H N
2
v m v H m 2, H O 2
A N N C
m A NH HN C
H p m
N H p
N
D PPO (7) D
m p m p
O 2
Protoporphyrin IX Proto’gen IX
Figure 58–4. The heme biosynthetic pathway. The subcellular distribution of the eight enzymes and their substrates and intermediates are shown;
enzymes within the light blue shading are located in the mitochondrion, and the others in the cytosol. The substrate positions that are changed are
shown in blue, bold lines. ALA, δ-aminolevulinic acid; Copro’gen, coproporphyrinogen; HMB, hydroxymethylbilane; PBG, porphobilinogen; Proto’gen,
protoporphyrinogen; Uro’gen, uroporphyrinogen. a, –CH COOH; p, –CH –CH –COOH; m, –CH ; v, –CH=CH ; carbon groups shown in red, carbon
2
2
2
3
2
atom derived from the α-carbon of glycine; *, location of the α-carbon atom from glycine in the pyrrole ring that undergoes reversion. Step 1, ALA
synthase (ALAS); step 2, ALA dehydratase (ALAD); step 3, PBG deaminase (PBGD); step 4, uro’gen III cosynthase (UROS); step 5, uro’gen decarboxylase
(UROD); step 6, copro’gen oxidase (CPO); step 7, proto’gen oxidase (PPO); step 8, ferrochelatase (FECH).
site. Subsequently the DNA sequences were modified to encode gene- contains an iron-responsive element in its 5′-untranslated region, sim-
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specific regulatory regions, functioning mostly at the amino termini. 22 ilar to mRNAs encoding ferritin and the transferrin receptor (Chap.
The promoter in the human ALAS2 gene contains several puta- 42). Gel retardation analysis shows that the iron-responsive element
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tive erythroid-specific cis-acting elements including both a GATA-1 in ALAS2 mRNA is functional and suggests that translation of the
and an NF-E2 binding site. 22,23 Both GATA-1 and NF-E2 are erythroid erythroid-specific mRNA is directly linked to the availability of iron, or
transcription factors that also bind other DNA sites, such as the pro- heme, in erythroid cells. 26
moters of the human β-globin, porphobilinogen deaminase (PBGD), In the liver, synthesis of ALAS1 is induced by a variety of chemi-
and uroporphyrinogen synthase (UROS) genes. Thus, expression of cals, including drugs and steroids that increase the demand for hepatic
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ALAS2 is under the regulatory influence of erythroid transcription CYPs. Upstream enhancer elements in the ALAS1 gene and certain
factors such as GATA-1 and is coordinated with expression of other hepatic CYP genes respond to inducing chemicals and interact with
genes involved in hemoglobin synthesis. Additionally, ALAS2 mRNA the pregnane X receptor (PXR). Hemin represses synthesis of ALAS1
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