Hemoglobin Dan Mioglobin

HEMOGLOBIN
MYOGLOBIN
DE PA RT ME N T O F BI O CH E MIS TRY
U N I V E RSITY O F M U H A M MA DIYA H SU M AT E RA U TA RA
2018
Kasus
Seorang anak perempuan berusia 7
tahun dibawa ibunya berobat ke RS
karena selau lemas dan wajahnya yang
tampak pucat. Dari hasil pemeriksaan
morfologi eritrosit dijumpai sebagian
eritrosit berbentuk tidak normal yaitu
seperti bulan sabit.
Apakah yang terjadi pada anak tersebut?
Myoglobin
Myoglobin
Protein completely
surrounds heme.
Function of protein:
◦ ↑ heme solubility.
◦ ↓ heme oxidation
(Fe2+ → Fe3+)
◦ metmyoglobin inactive.
◦ ↓ CO binding.
Hemoglobin
Quaternary structure of deoxy- and oxyhemoglobin
T-state R-state
1
0.8
Bohr Effect
log Q
0.6
pH = 7.5
pH = 7.2
pH = 6.8
Oxygen affinity sensitive to pH. 0.4
↓ pH; ↑ pO2,50 (lowers

sensitivity). 0.2
D94 ↔ H146 salt bridge in T state

H146 D94 0
only. 0 20 40 60 80 100 120
Excess H+ forms salt bridge, favors log pO2
deoxy state.
CO2 is Coupled to Bohr Effect
In Tissue
CO2 is bound by Hb or converted to bicarbonate by carbonic anhydrase.
Buffers blood pH.
Hb binds 2H+ / 4 O2 released, also buffers (Bohr effect).
In Lungs
Low pCO2; reaction reverses;
CO2 and H+ released from Hb,
pO2,50 decreased (increased oxygen affinity).
2,3-Bisphosphoglycerate (BPG) Stabilizes
the T Structure of Hemoglobin
A low PO2 in peripheral tissues promotes the synthesis of 2,3-BPG in
erythrocytes from the glycolytic intermediate 1,3-BPG.
The hemoglobin tetramer binds one molecule of BPG in the central cavity
formed by its four subunits.
However, the space between the H helices of the chains lining the cavity is
sufficiently wide to accommodate BPG only when hemoglobin is in the T state.
BPG acts as a “wedge” and drives the R state to the T state.
Forces release of bound O2 in active tissue.
NUMEROUS MUTATIONS AFFECTING HUMAN
HEMOGLOBINS HAVE BEEN
IDENTIFIED
Mutations in the genes that encode the α or β subunits of
hemoglobin potentially can affect its biologic function.
However, almost all of the over 900 known genetic mutations
affecting human hemoglobins are both extremely rare and benign,
presenting no clinical abnormalities.
When a mutation does compromise biologic function, the condition
is termed a hemoglobinopathy.
It is estimated that more than 7% of the globe's population are
carriers for hemoglobin disorders.
Methemoglobin & Hemoglobin M
In methemoglobinemia, the heme iron is ferric rather
than ferrous. Methemoglobin thus can neither bind nor
transport O2 .
Normally, the enzyme methemoglobin reductase
reduces the Fe3+ of methemoglobin to Fe2+ .
Methemoglobin can arise by oxidation of Fe2+ to Fe3+
as a side effect of agents such as sulfonamides, from
hereditary hemoglobin M, or consequent to reduced
activity of the enzyme methemoglobin reductase.
In hemoglobin M, histidine F8 (His F8) has been replaced by tyrosine.
The iron of HbM forms a tight ionic complex with the phenolate
anion of tyrosine that stabilizes the Fe3+ form.
In -chain hemoglobin M variants, the R-T equilibrium favors the T
state.
Oxygen affinity is reduced, and the Bohr effect is absent. -Chain
hemoglobin M variants exhibit R-T switching, and the Bohr effect is
therefore present.
Mutations that favor the R state (eg, hemoglobin Chesapeake)
increase O2 affinity. These hemoglobins therefore fail to deliver
adequate O2 to peripheral tissues. The resulting tissue hypoxia leads
to polycythemia, an increased concentration of erythrocytes.
Hemoglobin S
In HbS, the nonpolar amino acid valine has replaced the polar surface residue Glu6 of the β subunit,
generating a hydrophobic "sticky patch" on the surface of the β subunit of both oxyHbS and
deoxyHbS.
Both HbA and HbS contain a complementary sticky patch on their surfaces that is exposed only in the
deoxygenated T state. Thus, at low PO2 , deoxyHbS can polymerize to form long, insoluble fibers.
Binding of deoxyHbA terminates fiber polymerization, since HbA lacks the second sticky patch
necessary to bind another Hb molecule.
These twisted helical fibers distort the erythrocyte into a characteristic sickle shape, rendering it
vulnerable to lysis in the interstices of the splenic sinusoids.
They also cause multiple secondary clinical effects. A low PO 2 such as that at high altitudes
exacerbates the tendency to polymerize.
Emerging treatments for sickle cell disease include inducing HbF expression to inhibit the
polymerization of HbS, stem cell transplantation, and, in the future, genetherapy.
Genetic disease: Sickle-cell Anemia
Identifying cause of genetic mutation, e.g.Sickle cell anemia
✦ Due to a 1 base pair change in the gene for the β subunit of
hemoglobin
Hb-A:
...ATG GTG CAC CTG ACT CCT GAG GAG AAG TCT GCC GTT ACT...
Hb-S:
... ATG GTG CAC CTG ACT CCT GTG GAG AAG TCT GCC GTT ACT...
Other Hemoglobin variants
i. Hemoglobin S …….. ß6 Glu  Val
ii. Hemoglobin C………. ß6 Glu  Lys – very little consequence
iii. Hemoglobin E ………. ß26 Glu Lys – very little consequence
iv. Hemoglobin Constant Spring (a-globin chain that is abnormally
long)
v. Hemoglobin H …(ß4)- high affinity, doesn’t deliver O2 very well
vi. Hemoglobin Barts………(γ4) – fetus usually dead before birth
Biomedical Implications
Myoglobinuria
Following massive crush injury, myoglobin released from damaged
muscle fibers colors the urine dark red.
Myoglobin can be detected in plasma following a myocardial
infarction, but assay of serum enzymes provides a more sensitive
index of myocardial injury.
Anemias
Anemias, reductions in the number of red blood cells or of
hemoglobin in the blood, can reflect impaired synthesis of
hemoglobin (eg, in iron deficiency) or impaired production of
erythrocytes (eg, in folic acid or vitamin B12 deficiency).
Diagnosis of anemias begins with spectroscopic measurement of
blood hemoglobin levels.
Thalassemias
The genetic defects known as thalassemias result from the partial or total
absence of one or more α or β chains of hemoglobin.
Over 750 different mutations have been identified, but only three are common.
Either the α chain (alpha thalassemias) or β chain (beta thalassemias) can be
affected.
A superscript indicates whether a subunit is completely absent (α0 or β0 ) or
whether its synthesis is reduced (α+ or β+ ). Apart from marrow transplantation,
treatment is symptomatic.
Certain mutant hemoglobins are common in many populations, and a patient
may inherit more than one type.
Hemoglobin disorders thus present a complex pattern of clinical phenotypes.
Glycated Hemoglobin (HbA1c )
When blood glucose enters the erythrocytes, it glycates the -amino group of
lysine residues and the amino terminals of hemoglobin.
The fraction of hemoglobin glycated, normally about 5%, is proportionate to
blood glucose concentration.
Since the half-life of an erythrocyte is typically 60 days, the level of glycated
hemoglobin (HbA1c ) reflects the mean blood glucose concentration over the
preceding 6–8 weeks.
Measurement of HbA1c therefore provides valuable information for
management of diabetes mellitus.
References
Devlin MT, Textbook of Biochemistry with Clinical Correlations, 5th ed, Willey Liss, 2002
Murray RK, Granner DK, Mayes PA, Harper’s Biochemistry, 26th ed., Lange Medical Books, Mc
Graw-Hill, 2003
Lubert S, Biochemistry, 5th ed., Freeman & Co, New York, 2002

Hemoglobin Dan Mioglobin

Uploaded by

Copyright:

Available Formats

Hemoglobin Dan Mioglobin

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Hemoglobin Dan Mioglobin

Uploaded by

Copyright:

Available Formats

HEMOGLOBIN

↓ pH; ↑ pO2,50 (lowers

D94 ↔ H146 salt bridge in T state

You might also like