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BIOCHEMISTRY OF PORPHYRIA
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Heme
Heme Biosynthesis Pathway
Heme Precursors
Biochemical Aspects
Delta ALA
Porphobilinogen [PBG]
Heme Defects
Disturbances of Heme

PORPHYRIA FACTS: BIOCHEMISTRY OF PORPHYRIA

HEME

What is heme?

Heme is a vital molecule for all of the body's organs.

It is a component of hemoglobin, the molecule that carries oxygen in the blood.

SOURCE:
Disease Resource Book
Alliance Medical Systems
1998
++++++++++++

The most important function of porphyrins is as components of heme.

Heme is made from iron + protoporphyrin.

Hemoglobin is made up of four globin proteins + 4 heme groups.

Oxygen binds to the iron in the heme molecules.

Various kinds of porphyrins exist with the same basic structure, but with slightly
different chemical appearance.

The major biochemical pathway includes conversions from porphyrins to
delta-ALA, then to PBG, then uroporphyrin, then coproporphyrin, then
protoporphyrin, and finally into the end product -- heme.

Each step requires the presence of a specific enzyme.

If any of the enzymes are deficient (because of a genetic disease or inhibition by
a toxic substance), these intermediates build up, and a type of porphyria results.

SOURCE:
Randall Moreton PhD
Biochemistry & Molecular Biology
+++++++++++


Heme is the all-important iron-binding molecule essential for the proper
function of many proteins, including hemoglobin (oxygen-transport), cytochrome
c (energy production) and cytochrome P-450 (detoxification). "

SOURCE:
J. Alexander Bralley et. al.
MetaMetrix
Testing for Toxic Metals
+++++++++++++

The cytochrome P450" enzyme system,uses heme to detoxify chemicals in the
liver and other vital organs

SOURCE:
Evaluating Disorders of Porphyrin Metabolism
Albert Donnay, Grace Ziem
MCS Services
+++++++++++++



The best known function of heme is its oxygen binding and transport in
hemoglobin, and erythroblasts synthesize 85% of the total body heme is the
bone marrow.

In addition, heme is involved in the mitochondrial respiratory chain where it
transports electrons to cytochromes.

CYP enzymes, which metabolize a large number of clinically important drugs as
well as several endogenous and exogenous substances, contain heme.

Tryptophan pyrrolase, which catalyses the oxidation of tryptophan, is also a
heme-dependent enzyme.

SOURCE:
Molecular genetics of acute intermittent
porphyria in Finland
Sami Mustajoki
Division of Endocrinology,
Department of Medicine,
University of Helsinki &
Department of Human Molecular Genetics,
National Public Health Institute, Finland
+++++++++++++++

Heme is the prosthetic group of many hemeproteins.

SOURCE:
Juha Kere, M.D., Ph.D.
Finnish Genome Center
University of Helsinki, Finland
++++++++++++++

Heme is involved in the mitochondrial respiratory chain where it transports
electrons to cytochromes.

SOURCE:
Juha Kere, M.D., Ph.D.
Finnish Genome Center
University of Helsinki, Finland
+++++++++

Heme is synthesized from smaller molecules through several enzyme-catalyzed
steps in a biochemical pathway.

SOURCE:
Painful porphyrins
Julie L. McDowell
Diseases and disorders
American Chemical Society
2001
+++++++++++

Heme is synthesized in largest amounts by the bone marrow, where it is
incorporated into hemoglobin, which is an oxygen transport protein, and by the
liver, where most is incorporated into cytochromes, which are electron transport
proteins.
SOURCE:
MERCK HANDBOOK
1995-2002
Merck & Co., Inc.,
Whitehouse Station, NJ
++++++++++



This type of iron - porphyrin complex, when attached to the protein called globin
is called hemoglobin.

SOURCE:
The Canadian Porphyria Foundation Inc.
Neepawa, Manitoba, Canada
+++++++++++

In the bone marrow, heme is made in erythroblasts and reticulocytes that still
contain mitochondria, whereas circulating erythrocytes lack mitochondria and
cannot form heme.

SOURCE:
MERCK HANDBOOK
1995-2002
Merck & Co., Inc.,
Whitehouse Station, NJ
+++++++++++++

Heme transports hemoglobin.

SOURCE:
Juha Kere, M.D., Ph.D.
Finnish Genome Center
University of Helsinki, Finland
++++++++++++++

Hemoglobin is the protein that carries oxygen.

Hemoglobin is found within the red blood cells.

SOURCE:
Vitamins and Minerals:
Healthy Diet & Safe Supplementation
Denise Mortimore
Element
2001
++++++++++

Disorders of porphyrin metabolism can have a disruptive effect on numerous
processes that rely on heme and hemoglobin.

SOURCE:
Evaluating Disorders of Porphyrin Metabolism
Albert Donnay, Grace Ziem
MCS Services
+++++++++++++++++

In the bone marrow, heme is made in erythroblasts and reticulocytes that still
contain mitochondria, whereas circulating erythrocytes lack mitochondria and
cannot form heme.

SOURCE:
MERCK HANDBOOK
1995-2002
Merck & Co., Inc.,
Whitehouse Station, NJ
++++++++++++


Heme is most noted for the part that it plays in the hemoglobin, which is the
body's oxygen delivery system.

Hepatic [liver] heme is necessary for the manufacture of microsomal cytochrome
P-450.

The P-450 system is critical in the detoxification of drugs and chemicals.

Chemicals and drugs that adversely effect cytochrome P-450 production are
also known as porphyrinogenic.


SOURCE:
Elsevier
North Holland Biomedical Press
Amsterdam, The Netherlands
1979
++++++++++++

Tryptophan pyrrolase is a heme enzyme.

This enzyme has a relaytively low affinity for its prosthetic group, heme.

It normally exists in the liver.

SOURCE:
D. Montgomery Bissell
Hepatic Porphyrias
Chapter 31
Diseases of the Liver
6th Edition / Lippincott
+++++++++++++



Tryptophan pyrrolase, which catalyses the oxidation of tryptophan, is a
heme-dependent enzyme.

SOURCE:
Juha Kere, M.D., Ph.D.
Finnish Genome Center
University of Helsinki, Finland
+++++++++++++++

With reduced heme production, reduced oxygen transport may reduce
metabolism, thus reducing body temperature, further interfering with P450
and other enzymatic systems.

SOURCE:
Porphyria
Greek for "Purple Urine"
Orthomolecular Medicine
+++++++++++

When clinically active, and in some cases even when latent or in clinical
remission, porphyrias induce high levels of heme precursors in blood, urine,
and/or stool.

When a person is inactive general levels remain near or within normal levels.

SOURCE:
Environmental Chemical Exposures and Disturbances of Heme Synthesis
Ralph D. Ellefson et. al.
Department of Laboratory Medicine
Mayo Clinic and Mayo Foundation
Rochester, Minnesota
++++++++++

Heme is synthesized in every eukaryotic and prokaryotic cell and it carries out
many important biologic functions.

It is the prosthetic group of many hemeproteins.

SOURCE:
Molecular genetics of acute intermittent
porphyria in Finland
Sami Mustajoki
Division of Endocrinology,
Department of Medicine,
University of Helsinki &
Department of Human Molecular Genetics,
National Public Health Institute, Finland
+++++++++++++

How is heme produced?


These organic porphyrin compounds are combined with metals such as
magnesium in the plant kingdom to produce chlorophyll and with iron in the
animal kingdom to produce heme.

SOURCE:
The Canadian Porphyria Foundation Inc.
Neepawa, Manitoba, Canada
++++++++++++++

Where does heme develop?

Heme biosynthesis occurs almost entirely in the liver and bonemarrow and
is composed by eight reactions, each one of these being catalyzed by an
especific enzyme.

SOURCE:
The Porphyrias
Anderson, Karl E
Cecil Textbook of Medicine,
13th ed. Mc Graw Hill,
1994
+++++++++++++++

Most heme is made in the bone marrow.


SOURCE:
Evaluating Disorders of Porphyrin Metabolism
Albert Donnay, Grace Ziem
MCS Services
+++++++++++++

85% of the total body heme is the bone marrow.

SOURCE:
Juha Kere, M.D., Ph.D.
Finnish Genome Center
University of Helsinki, Finland
+++++++++++++

Iron is a component of heme.

SOURCE:

Diet and Nutrition in Porphyria
Dr. Karl E. Anderson
American Porphyria Foundation
Houston, Texas
++++++++++++

Where are the heme making porphyrins located?

They are involved in the control of the electron transport systems of the
organism and are localized in the intracellular organelles called mitochondria.

SOURCE:
The Canadian Porphyria Foundation Inc.
Neepawa, Manitoba, Canada
+++++++++++++

The mitochondria is an overseer of the production and outlet of energy
used for cell metabolism in the human body.

SOURCE:
Robert Johnson MD
Internal Medicine
+++++++++++++

The mitochondria influence the production, accumulation and utilization of the
energy needed for cell metabolism.

SOURCE:

The Canadian Porphyria Foundation Inc.
Neepawa, Manitoba, Canada
++++++++++

Recently, the mechanism of the heme-controlled transcription system was
demonstrated, which suggests that the indirect effects of environmental
hazards are also important for elucidating toxicity, i.e., the hazards can affect
cell functions through such biological mediators as regulatory heme.

It is, therefore, probable that toxicology in the future will focus on biological
systems such as gene regulation and signal transduction systems.

SOURCE:
Lead, chemical porphyria, and heme as a biological mediator.
Fujita H, Nishitani C, Ogawa K.
Laboratory of Environmental Biology
Hokkaido University School of Medicine
Sapporo, Japan
Tohoku Journal of Exprimental Medicine
2002 Feb;196(2):53-64
++++++++++



Hematopathology is not only the study of disease of the blood and bone marrow,
but also of the organs and tissues which employ blood cells as principal
effectors of their physiologic functions.

Such would include the lymph nodes, spleen, thymus, and the many foci of
lymphoid tissue found along the aerodigestive tract.

Generally two types of medical subspecialists intensively practice in this area,
the hematologist and the hematopathologist. "

SOURCE:

Blood Cells and the CBC
Ed Uthman, MD
Diplomate
American Board of Pathology
+++++++++++++

The most important function of porphyrins is as components of heme.

Various kinds of porphyrins exist with the same basic structure, but with slightly
different chemical appearance.

The major biochemical pathway includes conversions from porphyrins to
delta-ALA then to PBG, then uroporphyrin, then coproporphyrin, then
protoporphyrin, and finally into the end product, heme.

Each step requires the presence of an enzyme. If any of the enzymes are
deficient (because of a genetic disease or inhibition by a toxic substance), a type
of porphyria results.

SOURCE:

Clarisse Cook

Biochemistry & Molecular Biology

++++++++++++++++++++



What is heme?

Heme is the all-important iron-binding molecule essential for the proper function

of many proteins, including hemoglobin (oxygen-transport), cytochrome c
(energy production) and cytochrome P-450 (detoxification).

SOURCE:

J. Alexander Bralley et. al.

MetaMetrix

Testing for Toxic Metals

+++++++++++++++++++++++++++++++++++++

Heme is a component of hemoglobin, the molecule that carries oxygen in the
blood.

SOURCE:

Lister Hill National Center for

Biomedical Communications

National Institutes of Health

Department of Health & Human Services

++++++++++++++

Heme is the prosthetic group of many hemeproteins.

SOURCE:

Juha Kere, M.D., Ph.D.

Finnish Genome Center

University of Helsinki, Finland

++++++++++++++

Heme is most noted for the part that it plays in the hemoglobin, which is the
body's oxygen delivery system.

Hepatic [liver] heme is necessary for the manufacture of microsomal cytochrome
P-450.

The P-450 system is critical in the detoxification of drugs and chemicals.

Chemicals and drugs that adversely effect cytochrome P-450 production are
also knownas porphyrinogenic.

SOURCE:
Elsevier
North Holland Biomedical Press
Amsterdam, The Netherlands
1979
++++++++++++

Most heme is made in the bone marrow.

SOURCE:
Evaluating Disorders of Porphyrin Metabolism
Albert Donnay, Grace Ziem
MCS Services
+++++++++++++

Heme exists as hemoglobin in the bone marrow and red blood cells but has
other functions in other tissues such as the liver.

The type of porphyria present is determined by which enzyme is deficient.

SOURCE:
Dr. Karl E. Anderson
University of Texas Medical School
Galveston, TX
++++++++++++

Most of the body’s heme is found in the bone marrow.

SOURCE:
Robert JOhnson MD
Internal Medicine
+++++++++++++++

85% of the total body heme is the bone marrow.

SOURCE:
Juha Kere, M.D., Ph.D.
Finnish Genome Center
University of Helsinki, Finland
+++++++++++++++

The best known function of heme is its oxygen binding and transport in
hemoglobin, and erythroblasts synthesize 85% of the total body heme is the
bone marrow.

SOURCE:
Molecular genetics of acute intermittentporphyria in Finland
Sami Mustajoki
Division of Endocrinology,
Department of Medicine,
University of Helsinki &
Department of Human Molecular Genetics,
National Public Health Institute, Finland
++++++++++++++

Heme is involved in the mitochondrial respiratory chain where it transports
electrons to cytochromes. CYP enzymes, which metabolize a large number of

clinically important drugs as well as several endogenous and exogenous
substances, contain heme.

SOURCE:
Molecular genetics of acute intermittent porphyria in Finland
Sami Mustajoki
Division of Endocrinology,
Department of Medicine,

University of Helsinki &
Department of Human Molecular Genetics,
National Public Health Institute, Finland
+++++++++++++++


The most populous of the circulating white cells, they are also the most short
lived in circulation.

After production and release by the marrow, they only circulate for about eight
hours before proceeding to the tissues (via diapedesis), where they live for
about a week, if all goes well.

They are produced as a response to acute body stress, whether from infection,
infarction, trauma, emotional distress, or other noxious stimuli.

When called to a site of injury, they phagocytose invaders and other
undesirable substances and usually kill themselves in the act of doing in the
bad guys.

SOURCE:
Blood Cells and the CBC
Ed Uthman, MD
Diplomate
American Board of Pathology
+++++++++++


HEME BIOSYNTHESIS PATHWAY

Porphyria is a disorder of heme synthesis.

Porphyria is accompanied by an abnormal
accumulation of porphyrins which may be
measured in the urine, plasma and blood.

+++++++++++++++++++

Heme synthetic pathway

A biosynthetic pathway in which simple substances
are converted to heme.

The pathway begins with ALA and ends with heme.

The intermediates chemical substances on this
pathway are known as the porphyrins.
+++++++++++++++++++++

Heme synthesis

The production of heme by the heme synthetic pathway.
++++++++++++++++++++

Induction

Induction refers to the process whereby the synthesis
(or production) of chemical compounds is increased
(i.e. induced) in the body in response to appropriate
triggering factors.

Two forms of induction are important in porphyria.

Heme synthesis is induced in response to an
increased need for heme, which may aggravate
the porphyria.

Secondly, a group of enzymes called the cytochrome
P450 enzymes are induced in response to the
administration of many drugs.

Since the cytochrome P450s require heme,
administration of those drugs results in increased
heme synthesis which may aggravate porphyria
and even result in an acute attack.
+++++++++++++++++++++

Heme

Heme is the final product on the heme synthetic pathway.

It is a molecule closely related to the porphyrins
and is essential for life.

It constitutes a major part of haemoglobin, which
is responsible for the carriage of oxygen, and also
forms a vital part of many enzymes responsible for
critical biochemical processes in the body.

Spelled "heme" in the United States, in European
literature the spelling is haem.
++++++++++++++++++++

Enzymes

A protein which serves as a biological catalyst,
bringing about the conversion of one chemical
substance to another.

Eight enzymes are found within the haem synthetic
pathway,and a defect in each enzyme is associated
with a specific type of porphyria.

The genetic code needed to make an enzyme
is written on a gene, which is a specific sequence '
of DNA.

In most instances, an enzyme is defective
because of a mutation within the gene for
that enzyme.
+++++++++++++++++++++++

Inhibition of enzymes

Inhibition is a technical term describing the
process whereby interference with an enzyme
results in decreased activity of that enzyme.

For example, in many patients with porphyria
cutanea tarda, the enzyme UROD is inhibited as a
consequence of excessive iron accumulation in the liver.
+++++++++++++++++

Precursors

The porphyrin precursors are aminolaevulinic acid
(ALA) and porphobilinogen (PBG).

These are the first two intermediate substances on the heme synthetic pathway.

They are known as precursors as chemically they
have not yet attained the tetrapyrrole configuration
typical of the porphyrins.

The precursors are particularly elevated in patients
with acute intermittent porphyria and in patients
with variegate porphyria and hereditary coproporphyria
experiencing the acute attack.

The porphyrin precursors are excreted in urine and are therefore measured in
urine samples.
++++++++++++++++++++

Aminolaevulinic acid (ALA)

Aminolaevulinic acid is the first precursor on
the heme synthetic pathway.

Two simple substances, glycine and succinyl-CoA,
combine to form one molecule of ALA.

Following this, two molecules of ALA combine to
form porphobilinogen (PBG). ALA and PBG are
usually measured together in the urine.
+++++++++++++++++++++++

Acute attacks

This is a phase of the acute porphyrias (acute
intermittent porphyria, hereditary coproporphyria,
variegate porphyria and ALA dehydratase deficiency
porphyria) in which the block in haem synthesis is
particularly severe.

The porphyrin precursors ALA and PBG rise to very
high levels and the patient becomes ill with a
syndrome manifesting with severe abdominal
pain, a raised blood pressure and pulse rate,
and may potentially developed severe nerve
damage with paralysis.
+++++++++++++++++++++

Porphobilinogen

Porphobilinogen (PBG). PBG is the second
precursor on the haem synthetic pathway.

It is formed by the condensation of two
molecules of ALA.

Four molecules of PBG are in turn
combined and converted to uroporphyrin.

Acute intermittent porphyria is frequently
associated with elevated levels of ALA
and PBG; levels of ALA and PBG also arise
during the acute attack of variegate porphyria
and hereditary coproporphyria.

PBG is commonly measured in the urine.
+++++++++++++++++++++++++

Uroporphyrin


Uroporphyrin is the third chemical substance
and the first porphyrin on the heme synthetic pathway.

A tetrapyrrole containing eight carboxylic side chains.

Large amounts of uroporphyrin are excreted
in the urine in normal subjects, and these
amounts are increased in some forms of porphyria.
+++++++++++++++++++++++++


Pentacarboxylic porphyrin

The sixth chemical substance and the
fourth porphyrin on the heme synthetic pathway.

A tetrapyrrole containing five carboxylic
acid side chains.

Pentacarboxylic porphyrin is found in small
amounts in urine and plasma.
++++++++++++++++++++++++++

Coproporphyrin

The seventh chemical substance and the fifth
porphyrin on the heme synthetic pathway.

A tetrapyrrole containing four carboxylic side
chains.

Coproporphyrin is excreted in both urine and stool,
and is commonly measured by porphyrin laboratories
in urine, stool, red blood cells and plasma.
++++++++++++++++++++++

Protoporphyrin


The eighth and final chemical substance on the heme
synthetic pathway before haem itself.

A tetrapyrrole containing two carboxylic side chains.

Protoporphyrin is excreted in the stool, and
is commonly measured by porphyrin
laboratories in stool and red blood cells.
+++++++++++++++++++++

Tetrapyrroles


A chemical substance consisting of four
pyrrole rings, joined together into a single large ring known as a macrocycle.

All the porphyrins are tetrapyrroles.

SOURCE:
Felix Gustave PhD
Biochemistry
+++++++++++++++

HEME PRECURSORS

Precursors

When clinically active, and in some cases even when latent or in clinical
remission, porphyrias induce high levels of heme precursors in blood, urine,
and/or stool.

When a person is inactive general levels remain near or within normal levels.

SOURCE:
Environmental Chemical Exposures and Disturbances of Heme Synthesis
Ralph D. Ellefson et. al.
Department of Laboratory Medicine
Mayo Clinic and Mayo Foundation
Rochester, Minnesota
++++++++++++

Porphyrin precursors are natural chemicals that normally do not accumulate in
the body.

Precisely which one of these porphyrin chemicals builds up depends upon the
type of Porphyria that a patient has.

SOURCE:
Acute Intermittent Porphyria
National Organization for Rare Disorders
+++++++++++++

Heme precursors are synthesized in excess in porphyria.

SOURCE:
Erythropoietic and hepatic porphyrias.
Gross U, Hoffmann GF, Doss MO.
Division of Clinical Biochemistry,
Faculty of Medicine,
Philipps University,
Marburg, Germany.
++++++++++++++

Synthesis of heme precursors are in the excess porphyrins.

SOURCE:
Journal of Inherited Metabolic Disease
2000 Nov;23(7):641-61
++++++++++++++


Precursors" are substances called ALA and PBG which are measured to check
the activity of the first two enzymes in the heme pathway.


SOURCE:
Evaluating Disorders of Porphyrin Metabolism
Albert Donnay, Grace Ziem
MCS Services
++++++++++++++++

The precursors of heme are glycine and succinyl coenzyme

A which are combined by aminolevulinic acid (ALA) synthase to form
5-aminolevulinic acid in the presence of the cofactor pyridoxal 5'-phosphate.

SOURCE:
Marja-Liisa Savontaus, Ph.D.
Department of Medical Genetics
University of Turku, Finland
++++++++++++




How the porphyrin precursors lead to these acute attack symptoms is unknown.

SOURCE:
Medicine Journal
February 22 2002
Volume 3, Number 2
"Acute intermittent porphyria"
Thomas G DeLoughery, MD
Associate Director
Department of TransfusionMedicine
Division of Clinical Pathology
Associate Professor
Department of Medicine
Division of Hematology and Medical Oncology
Oregon Health Sciences University
Portland, Oregon
+++++++++++++

How does a precusor cause an acute attack"

How the porphyrin precursors lead to these acute attack symptoms is unknown.

SOURCE:
Medicine Journal
February 22 2002
Volume 3, Number 2
+++++++++++


Medical science has to date not determined how porphyrin precursors work.

SOURCE:
Robert Johnson MD
Internal Medicine
+++++++++++

The way porphyrin precursor cause an acute attack is unknown.

SOURCE:
Acute intermittent porphyria"
Thomas G DeLoughery, MD
Associate Director
Department of TransfusionMedicine
Division of Clinical Pathology
Associate Professor
Department of Medicine
Division of Hematology and Medical Oncology
Oregon Health Sciences University
Portland, Oregon
++++++++++

What is the precursor of heme?

Four small pyrrole rings become joined through a series of enzymatic reactions
to ultimately form a large ring configuration or tetrapyrrole compound called
protoporphyrinogen that, in turn, is the precursor of heme.

SOURCE:
The Canadian Porphyria Foundation Inc.
Neepawa, Manitoba, Canada
++++++++++++

The precursors of heme are glycine and succinyl coenzyme A which are
combined by aminolevulinic acid (ALA) synthase to form 5-aminolevulinic
acid in the presence of the cofactor pyridoxal 5'-phosphate.

Next, two molecules of ALA are condensed to a monopyrrole porphobilinogen
(PBG) by ALA dehydratase.

SOURCE:
Molecular genetics of acute intermittent
porphyria in Finland
Sami Mustajoki
Division of Endocrinology,
Department of Medicine,
University of Helsinki &
Department of Human Molecular Genetics,
National Public Health Institute, Finland
+++++++++++

When clinically active, and in some cases even when latent or in clinical
remission, porphyrias induce high levels of heme precursors in blood, urine,
and/or stool.

When a person is inactive general levels remain near or within normal levels.


SOURCE:
Environmental Chemical Exposures and Disturbances of Heme Synthesis
Ralph D. Ellefson et. al.
Department of Laboratory Medicine
Mayo Clinic and Mayo Foundation
Rochester, Minnesota
++++++++++


Protoporphyrin synthesis cannot be enhanced by high ALA concentrations.

SOURCE:
"Glucose effect" and rate limitingfunction of uroporphyrinogen
synthase on porphyrin metabolism in hepatocyte culture: relationship with
human acute hepatic porphyrias.
Doss M, et. al.
++++++++++


Less than 10% of porphobilinogen is converted intoprotoporphyrin.

SOURCE:
"Glucose effect" and rate limiting function of uroporphyrinogen synthase on
porphyrin metabolism in hepatocyte culture: relationship with human acute
hepatic porphyrias.
Doss M, et. al.
+++++++++++

Uroporphyrinogen III cosynthase catalyzes the formation of uroporphyrinogen III
from HMB.

This involves an intramolecular rearrangement that reverses the orientation of
ring D (the pyrrole ring on the right end of the HMB molecule followed by closure
of the macrocycle to formuroporphyrinogen III.

When this enzyme is deficient, HMB can undergospontaneous closure of the
macrocycle without reversal of ring D, leading to formation of uroporphyrinogen
I. "

SOURCE:
MERCK HANDBOOK
1995-2002
Merck & Co., Inc.,
Whitehouse Station, NJ
++++++++++

In ALA-D and other disorders in which ALA accumulates, excess ALA may be
metabolized to coproporphyrin III in tissues other than the tissue of origin of the
excessALA.

Fecal porphyrin excretion is normal or marginally elevated.

SOURCE:
The Porphyrias
The Less Common Porphyrias
Endocrine and Metabolic Disorders
Merck Manual of Diagnosis
++++++++++++

Combining of glycine and succinyl - coenzyme A to form delta-aminolevulinic
acid (ALA), these molecules condense to form a single pyrrole ring structure
called porphobilinogen (PBG).

SOURCE:
The Canadian Porphyria Foundation Inc.
Neepawa, Manitoba, Canada
++++++++++

ALA-D is the rarest porphyria, resulting from a deficiency of ALA dehydratase.

SOURCE:
The Porphyrias
The Less Common Porphyrias
Endocrine and Metabolic Disorders
Merck Manual of Diagnosis
++++++++++

Increased levels of coproporphyrins can indicate congenital erythropoietic
porphyria orsideroblastic anaemia.

SOURCE:
Gray's Medical Encylcopedia
++++++++++

Erythropoiesis is a process of production of erythrocytes in the marrow in adult
mammals.

SOURCE:
Stedman's Medical Encyclopedia
The product of the reaction, ALA, diffuses into the cytoplasm.
Here the next several steps of heme synthesis occur.
SOURCE:
Delta-aminolevulinic acid synthase
Heme Synthesis
J. Bloomer.M.D.
January 1995
++++++++++

Delta-aminolevulinic acid synthase (ALA synthase)

The delta-aminolevulinic acid (pronounce) synthase (ALA synthase) reaction
occurs in the mitochondria.

SOURCE:
University of Utah Medical School
Department of Biochemistry
++++++++++++

There are two major means of regulating the activity of the enzyme.

The first is by regulating the synthesis of the enzyme protein.

This is important because its half life is only about one hour.

Enzyme synthesis is repressed by heme and hematin.

It is stimulated by barbiturates (as a result, these drugs exacerbate certain
porphyrias). steroids with a 4,5 double bond, such as testosterone and certain
oral contraceptives.

This double bond can be reduced by two different reductases to form either a
5-alpha or a 5-beta product.

Only the 5-beta product affects synthesis of ALA synthase. Since the 5-beta
reductase appears at puberty, some porphyrias are not manifested until this age.

Summary of regulation of heme synthesis.

The second control is feedback inhibition by heme and hematin, presumably by
an allosteric mechanism.

Hence, heme has a dual role in decreasing its own rate of synthesis.

The product of the reaction, ALA, diffuses into the cytoplasm, where the next
several steps of heme synthesis occur.

SOURCE:

University of Utah Medical School
Department of Biochemistry
++++++++++

The plasma porphyrin concentration may be increased in conditions in which
porphyrin excretion is impaired, such as renal failure and cholestasis.

SOURCE:
Front line tests for the investigation of suspected porphyria.
A C Deacon, G H Elder.
Journal of Clinical Pathology.
July 2001
v54 i7 p500.
++++++++++

Increased protoporphyrins may be seen in infection, thalassaemia, sideroblastic
anaemia, iron deficient anaemia, increased erythropoiesis and lead poisoning.

SOURCE:
Gray's Medical Encylcopedia
+++++++++

Porphobilinogen deaminase (PBGD) assembles the four rings of PBG in a
stepwise fashion in which the pyrrole ring A is first bound to the deaminase
followed by rings B, C and finally D.

The dipyrromethane cofactor, which arises from the autocatalytic coupling of two
molecules of PBG, iscovalently linked to the enzyme.

The cofactor functions as a primer to which thefour substrate molecules are
sequentially attached but is not itself incorporated
into the product, hydroxymethylbilane."

SOURCE:
Molecular genetics of acute intermittent
porphyria in Finland
Sami Mustajoki
Division of Endocrinology,
Department of Medicine,
University of Helsinki &
Department of Human Molecular Genetics,
National Public Health Institute, Finland
+++++++++++


The fourth enzyme, uroporphyrinogen III synthase, converts the highly unstable
hydroxymethylbilane to uroporphyrinogen III and in this reaction the linear
tetrapyrrole molecule is closed to form a ring.

In the absence of uroporphyrinogen III synthase, hydroxymethylbilane may
non-enzymatically close to uroporphyrinogen I. In normal circumstances,
this isoform is present only in minute amounts.

SOURCE:
Molecular genetics of acute intermittent
porphyria in Finland
Sami Mustajoki
Division of Endocrinology,
Department of Medicine,
University of Helsinki &
Department of Human Molecular Genetics,
National Public Health Institute, Finland
+++++++++++++

In AIP there is an autosomal hereditary metabolic aberration resulting from a
partial defect in the activity of the third-step enzyme (porphobilinogen
deaminase [PBGD]) during the course of heme synthesis.

SOURCE:
Beneficial Effect of Diabetes on
Acute Intermittent Porphyria
Folke Lithner, MD, PHD
Department of Internal Medicine
University Hospital, Umea, Sweden
+++++++++++

There is a partial defect in the activity of the third-step enzyme PBGD in the
synthesis of heme.

Diabetes Care
2002; 25:797-798

PBG deaminase catalyzes the condensation of four molecules of PBG to yield a
linear tetrapyrrole, hydroxymethylbilane (HMB).

There are two isozymes of PBG deaminase; one is present exclusively in
erythroid cells, whereas the other is in nonerythroid cells.

The two isoforms of PBG deaminase are encoded by distinct messenger RNAs
(mRNAs) that are transcribed from a single gene by alternate transcription and
splicing.

SOURCE:
MERCK HANDBOOK
1995-2002
Merck & Co., Inc.,
Whitehouse Station, NJ
+++++++++++

DELTA AMINOLEVULINIC ACID (ALA)

Delta ALA is the short name for Delta-aminolevulinic acid .

Delta-ALA is a chemical produced from amino acids in the liver.

Delta-aminolevulinic acid is the basic "building block" for the synthesis of
porphyrins.

The most important function of porphyrins are as components of heme (which is
the major building block of hemoglobin).

Oxygen binds to the iron in the heme molecules.

Various kinds of porphyrins exist with the same basic structure but with slightly
different chemical "side-chains".

The major biochemical pathway is delta-ALA --> PBG --> uroporphyrin -->
coproporphyrin --> protoporphyrin --> heme. Each step in the pathway requires a
specific enzyme.

If any of the enzymes is deficient, a type of porphyria results.

SOURCE:
Robert Johnson MD
++++++++++++
I

Delta-ALA, a protein produced by the liver, is increased when another protein
(an enzyme), has reduced function.

This may lead to a type of metabolic disorder called Porphyria

SOURCE:
Michael C. Milone, M.D., Ph.D.
Department of Pathology and Laboratory Medicine
University of Pennsylvania Medical Center
Philadelphia, PA.
++++++++++++

The delta-aminolevulinic acid synthase (ALA synthase) reaction occurs in the
mitochondria.

The substrates are succinyl CoA (from the tricarboxylic acid cycle) glycine (from
the general amino acid pool)

An essential cofactor is pyridoxal phosphate (vitamin B-6).

The reaction is sensitive to nutritional deficiency of this vitamin.

Drugs which are antagonistic to pyridoxal phosphate will inhibit it.

Such drugs include penicillamine and isoniazid (isonicotinic acid hydrazide)

The reaction occurs in two steps.

Condensation of succinyl CoA and glycine to form enzyme-bound
alpha-amino-beta-ketoadipate.

Decarboxylation of alpha-amino-beta-ketoadipate to form delta-aminolevulinate.

This is the rate-limiting reaction of heme synthesis in all tissues, and it is
therefore tightly regulated.

There are two major means of regulating the activity of the enzyme.

The first is by regulating the synthesis of the enzyme protein.

This is important because its half life is only about one hour.


Enzyme synthesis is repressed by heme and hematin.

It is stimulated by barbiturates (as a result, these drugs exacerbate certain
porphyrias). steroids with a 4,5 double bond, such as testosterone and certain
oral contraceptives.

This double bond can be reduced by two different reductases to form either a
5-alpha or a 5-beta product. Only the 5-beta product affects synthesis of ALA
synthase.

Since the 5-beta reductase appears at puberty, some porphyrias are not
manifested until this age.

The second control is feedback inhibition by heme and hematin, presumably by
an allosteric mechanism.
Hence, heme has a dual role in decreasing its own rate of synthesis.

The product of the reaction, ALA, diffuses into the cytoplasm, where the next
several steps of heme synthesis occur
SOURCE:
James Baggott, Ph.D
Department of Biochemistry
MCPHahnemann School of Medicine
Allegheny University of the Health Sciences
2900 Queen Lane
Philadelphia, PA 19129
+++++++++++++

PORPHOBILINOGEN PBG

Porphobilinogen is an intermediate in heme biosynthesis.

Porphobilinogen is made by condensing two -aminolevulinic acid (ALA)
molecules.

Subsequently, four porphobilinogen molecules condense to yield a
porphyrinogen called uroporphyrinogen



PBG is a substance (enzyme) used by the body to synthesize porphyrins
(nitrogen containing organisms).

The most important function of porphyrins is as components of heme. Heme is
made from iron + protoporphyrin.

Hemoglobin is made up of four globin proteins + 4 heme groups.
Oxygen binds to the iron in the heme molecules.

Various kinds of porphyrins exist with the same basic structure, but with slightly
different chemical appearance.

The major biochemical pathway includes conversions from porphyrins to
delta-ALA, then to PBG, then uroporphyrin, then coproporphyrin, then
protoporphyrin, and finally into the end product, heme.

Each step requires the presence of an enzyme.

If any of the enzymes are deficient (because of a genetic disease or inhibition by
a toxic substance), a type of porphyria results.
+++++++++++++++++++

HEME - ENZYME DEFECTS

Can enzyme deficiences cause porphyria?

The mutations identified account for the corresponding enzymatic deficiencies,
which may remain clinically silent throughout life.

SOURCE:
Erythropoietic and hepatic porphyrias.
Gross U, Hoffmann GF, Doss MO.
Division of Clinical Biochemistry,
Faculty of Medicine
Philipps University, Marburg, Germany.
Journal of Inherited Metabolic Disease
2000 Nov;23(7):641-61
++++++++++++

Porphyrias result from inherited or acquired deficiencies in any one of several
enzymes that synthesize heme.

When a given enzyme is absent or in short supply, porphyrins are shunted away
from heme synthesis into pathways that produce porphyrin by-products.

These by-products, in turn, build up in tissues and cause the clinical
manifestations of porphyria.

SOURCE:
Porphyria: Don't Forget to Look At the Skin
Dr. Michael W. Rich
Professor of Medicine
Internal Medicine
Northeastern Ohio Universities
College of Medicine, Rootstown
Summa Health System, Akron.
+++++++++



Enzyme deficiencies are usually inherited.

Environmental factors, such as drugs, chemicals, diet and sun exposure can,
depending on the type of porphyria, greatly influenced the severity of symptoms.

SOURCE:
Dr. Karl E. Anderson
University of Texas Medical School
Galveston, TX
+++++++++++++

All types of inherited porphyria are due to an identifible defect of an enzyme.

SOURCE:
Robert Johnson MD
Internal Medicine
+++++++++++++

Bone marrow cells express erythroid-specific forms of some pathway enzymes.

Erythroid-specific ALA synthase is regulated by an iron-responsive element in
the mRNA, and this accounts partly for tissue-specific regulation of heme
synthesis for hemoglobin formation.

SOURCE:
MERCK HANDBOOK
1995-2002
Merck & Co., Inc.,
Whitehouse Station, NJ
++++++++++++

The first enzyme and the last three enzyme defects are found in mitochondria;
the intermediate enzymes occur in the cytosol.

SOURCE:
MERCK HANDBOOK
1995-2002
Merck & Co., Inc.,
Whitehouse Station, NJ
+++++++++++

In all cases there is an identifiable abnormality of the enzymes.

There are only eight major enzymes that constitute the range of eight major
porphyrin types.

All other types of porphyria fall into one of these eight types.

Variances are due to the degree of the mutations to the enzymes.

In some types there is a mutation to more than one enzyme which will cause a
cross-over or over-lap of symptoms.

In PCT there are three major types with only one being inherited and the other
due to mutations caused the enzyme from external causes such as drugs,
alcohol and neurotoxins.

TAP is totally acquired through chemical exposure causing mutations of
otherwise healthy enzymes.

Medical science as we enter the millenium can still not explain the neurological
symptoms experienced in porphyria.

Such are especially puzzling since the metabolic defect is confined to
non-neural tissue, and no known diffusible intermediate can cause the
observed neurological symptoms of AIP,. HCP and VP."

SOURCE:
Understanding Porphyria Symptomology
M. Tokomyko MD
International Congress on Porphyria
Paris, France
July 1999
+++++++++

Enzyme deficiencies, of the pathway can accumulate and result in the
porphyrias.

SOURCE:
Primer on Laboratory Testing for Porphyrias
Dr. Karl E. Anderson
Porphyria Laboratory
University of Texas Medical Branch
++++++++++

Except for the first enzyme of the pathway, -aminolevulinate synthase (ALAS),
deficiencies in seven other enzymes are associated with the various forms of
porphyria.

SOURCE:
Molecular aspects of the inherited porphyrias
S. Sassa & A. Kappas
Journal of Internal Medicine 2000;
247: 169-178
+++++++++

An enzyme deficiency in any of the steps in the heme pathway inhibits heme
production, causing porphyrins to accumulate and clog the pathway.

A high accummulation of porphyrins is what causes porphyria.

SOURCE:
Painful porphyrins
Julie L. McDowell
Diseases and disorders
American Chemical Society
2001
+++++++++++

The main causes are enzyme deficiencies that lead to accumulation of heme in
the pathway.

SOURCE:

Metabolic Disorders
Porphyrias: Clinical Manifestations,
Diagnosis and Treatment
Bernardo Haddock Lobo Goulart
& Samanta Teixeira Basto
University Medical School, Brazil
++++++++++++

Each porphyria is characterised by a specific enzyme defect with altered
patterns of synthesis and excretion of porphyrins which accumulate and are
linked to clinical manifestations.

There is increased activity of the first and rate limiting enzyme 5 aminolaevulinic
acid (ALA) synthase.

SOURCE:
The Porphyrias
Alana Adams RPH
Welsh Drug Information Center
Cardiff, Wales, U.K.
+++++++++++++++

From the 1970s to the early 80s, almost all of the enzymes in the heme pathway
had been purified and characterized, and it was demonstrated that
elta-aminolevulinic aciduria is due to inhibition of delta-aminolevulinate
dehydratase by lead.

SOURCE:
Lead, chemical porphyria, and heme as a biological mediator.
Fujita H, Nishitani C, Ogawa K.
Laboratory of Environmental Biology
Hokkaido University School of Medicine
Sapporo, Japan
Tohoku Journal of Exprimental Medicine
2002 Feb;196(2):53-64
++++++++++


What is the exact action of porphyria formation?


As enzymatic efficiency falls with temperature, symptoms mimicking those of
genetic enzyme deficiencies as porphyria, may manifest themselves and
result in diagnostic inaccuracies.

SOURCE:
Porphyria
Greek for "Purple Urine"
Orthomolecular Medicine
+++++++++++++

The porphyrias are diseases that result from deficiencies of enzymes of the
heme biosynthetic pathway,

SOURCE:
Primer on Laboratory Testing for Porphyrias
Dr. Karl E. Anderson
Porphyria Laboratory
University of Texas Medical Branch
++++++++++++

Tryptophan pyrrolase is a heme enzyme.

This enzyme has a relaytively low affinity for its prosthetic group, heme.

It normally exists in the liver.

SOURCE:
D. Montgomery Bissell
Hepatic Porphyrias
Chapter 31
Diseases of the Liver
6th Edition / Lippincott
++++++++++++++

Tryptophan pyrrolase, which catalyses the oxidation of tryptophan, is also a
heme-dependent enzyme.

SOURCE:
Molecular genetics of acute intermittent
porphyria in Finland
Sami Mustajoki
Division of Endocrinology,
Department of Medicine,
University of Helsinki &
Department of Human Molecular Genetics,
National Public Health Institute, Finland
++++++++++++



Several problems can develop when the chemical reactions controlled by the
specific enzymes are defective.

If the enzyme process is slowed there may be a build up of potentially toxic
precursors and if the chemical reaction is too fast the end products may
accumulate in too high a concentration.

Sometimes the abnormal enzyme systems change the direction of the reaction
and produce abnormal metabolites.

These precursors and end products can be retained within the cell cytoplasm
where they may interfere with other metabolic processes or be sufficiently toxic
to cause the death of the cells.

Other water soluble compounds may be carried by the blood to other tissues
such as the skin where they can absorb abnormal amounts of radiant energy
and affect the body in a different way.

Most compounds are simply excreted in the stool and urine in abnormal amounts
without any clinical problem.

SOURCE:
The Canadian Porphyria Foundation Inc.
Neepawa, Manitoba, Canada
++++++++++

Enzyme deficiences can interfere with a variety of metabolic processes in turn
causing the triggering of the porphyrias.

SOURCE:
Robert Johnson MD
Internal Medicine
+++++++++++



Porphyrin enzymes are directly under the control of the DNA that is present in
the chromosomes contained within the nucleus of the cells.

The chromosomes have multiple condensations of coiled DNA which are called
genes.

The DNA in these genes makes RNA molecules, called messenger RNA which
regulate the production of proteins including these enzyme systems.

In general, each individual gene influences several enzyme functions, and for
the most part each enzyme system is under the control of multiple genes
although the most of the specific enzymes involved in porphyrin synthesis
seem to be encoded by single gene loci. .

If the DNA composition of the gene is defective or abnormal, the metabolic
functions that it controls probably will be defective as well.

SOURCE:
The Canadian Porphyria Foundation Inc.
Neepawa, Manitoba, Canada
++++++++++++

Many human diseases are due to defective enzyme functions.

SOURCE:
Robert Johnson MD
Internal Medicine
+++++++++++++

Since the multiple disease syndromes known as porphyria are all due to
defective enzyme functions, there are abnormal accumulations of a variety of
compounds involved in the metabolic pathway.

SOURCE:
The Canadian Porphyria Foundation Inc.
Neepawa, Manitoba, Canada
+++++++++++++

The porphyrias are composed by eight reactions, each one of these being
catalyzed by an especific enzyme.

SOURCE:
Metabolic Disorders
Porphyrias: Clinical Manifestations, Diagnosis and Treatment
Bernardo Haddock Lobo Goulart & Samanta Teixeira Basto
University Medical School, Brazil
+++++++++++

DISTURBANCES OF HEME

Certain chemicals can produce disturbances of heme synthesis that are
associated with alterations of subcellular structure and functions and
characteristic changes in patterns of heme-precursor excretion.

These measurable changes offer potential biological markers for detecting
harmful effects of specific chemical exposures while their biological effects are
still preclinical and potentially reversible.

Most clinicians, however, including specialists in occupational and
environmental medicine, are relatively uninformed about these phenomena.


SOURCE:
Environmental Chemical Exposures and Disturbances of Heme Synthesis
Michael R. Moore et. al.
Department of Medicine
University of Queensland
Coopers Plains
Queensland, Australia
+++++++++++

Toxicological studies from the 70s to the 90s focused on the direct effect of
hazards on biological molecules, such as the heme pathway enzymes, and
many environmental pollutants were proved to affect cytosolic heme.

SOURCE:
Lead, chemical porphyria,
and heme as a biological mediator.
Fujita H, Nishitani C, Ogawa K.
Laboratory of Environmental Biology
Hokkaido University School of Medicine
Sapporo, Japan
Tohoku Journal of Exprimental Medicine
2002 Feb;196(2):53-64
++++++++++++

Toxic chemicals, at any level of chronic exposure, affect human biochemistry.

Toxic chemical do affect heme synthesis and can and do trigger poprhyria
attacks."



SOURCE:
J. Alexander Bralley et. al.
MetaMetrix
Testing for Toxic Metals
++++++++++

The decrease in activity of erythrocyte aminolevulinate dehydratase observed in
diabetic ALA-D hepatic porphyria patients, may represent an additional and
useful parameter for the assessment of the severity of carbohydrate metabolism
impairment.

SOURCE:
Intternational Journal of Biochemistry and Cell Biology
1999
Mar-Apr;31(3-4):479-88
Delta aminolevulinate dehydratase (ALA-D) activity in
human and experimental diabetes mellitus.
Fernandez-Cuartero B et. al.
Department of Internal Medicine
University Complutense of Madrid,
Spain.
+++++

Deranged heme synthesis is beloieved to be the cause of the pathogenesis of
acute porphyria attacks.

SOURCE:
Robert Johnson MD
Internal Medicine
++++++++++

The pathogenesis of acute attacks is unknown, although it is hypothesized
that either ALA or its metabolites are neurotoxic, or deranged heme
synthesis in neurons impairs their function.

SOURCE:
Dr. Poh-Fitzpatrick, professor,
Department of Dermatology
Columbia University, New York
Dermatology Times,
Jun96, Vol. 17 Issue 6, p14, 2p
+++++++++



Heme biosynthesis in erythroid cells is regulated at least in part by the process
of cellular uptake of iron.


SOURCE:
MERCK HANDBOOK
1995-2002
Merck & Co., Inc.,
Whitehouse Station, NJ
++++++++++

Disorders of porphyrin metabolism can have a disruptive effect on numerous
processes that rely on heme and hemoglobin.

SOURCE:
Evaluating Disorders of Porphyrin Metabolism
Albert Donnay, Grace Ziem
MCS Services
+++++++++++++++++

Porphyrin and radiation-induced alteration of the heme biosynthetic pathway in
epidermal cells is mainly caused by affecting the ferrochelatase in these cells
rather than ALA synthase.

The photochemical reaction was partially related to reactive oxygen species
generated in the presence of porphyrin and radiation.

SOURCE:
Cutaneous Heme Metabolism;
Porphyrias; Photodermatoses
Dr. Henry Lim M.D.
New York University
School of Medicine
Department of Dermatology
550 First Avenue, New York, NY 10016
(212) 263-7300
+++++++++

The heme biosynthesis pathway contains eight steps and dysfunction in seven
of them is associated with a specific porphyria; defects in erythroid specific ALA
synthase result in X-chromosome linked sideroblastic anemia."

SOURCE:
Molecular genetics of acute intermittent porphyria in Finland
Sami Mustajoki
Division of Endocrinology,
Department of Medicine,
University of Helsinki &
Department of Human Molecular Genetics,
National Public Health Institute, Finland
++++++++++++++

Often, problems in the Cytochrome P-450 heme synthesis and detoxification
pathways show up as porphyria type problems.

SOURCE:
Porphyria
Greek for "Purple Urine"
++++++++++


Evaluation of cutaneous heme metabolism shows that the heme biosynthetic
pathway is present in epidermal and endothelial cells and is affected by
the Soret band of radiation.

This is demonstrated by the accumulation of porphyrin, the functional assay for
ferrochelatase, the Western blot for ferrochelatase, and the presence of
ferrochelatase mRNA.

SOURCE:
Cutaneous Heme Metabolism;
Porphyrias; Photodermatoses
Dr. Henry Lim M.D.
New York University
School of Medicine
Department of Dermatology
550 First Avenue, New York, NY 10016
(212) 263-7300
+++++++++++

The P450 system will break drugs down, using up the P450 feedstocks which
would otherwise be used to produce red blood.

SOURCE:
Porphyria
Greek for "Purple Urine"
Orthomolecular Medicine
+++++++++++


Mutational analysis is currently elucidating the relationship between disorders
and their autosomal dominant counterparts.

SOURCE:
Enzymatic defect in a child with hereditary hepatic porphyria
due to homozygous delta-aminolevulinic acid dehydratase deficiency:
immunochemical studies."
Fujita, H., S. Sassa, et al. (1987).
Pediatrics 80(6): 880-5.
++++++++++

Certain vegatables such as cabbage and brussel sprouts may contain
chemicals that can stimulate heme synthesis.

SOURCE:
Diet and Nutrition in Porphyria
Dr. Karl E. Anderson
American Porphyria Foundation
Houston, Texas
+++++++++


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