Lecture 59 Flashcards
Porphyrins are composed of 4 _____ rings linked by ____ bridges. ____ double bonds confer their color. The suffixes “-in” refers to ____ molecules, while “-ogen” refers to _____ molecules. Rings 1 and 2 have methyl and _____ groups, while rings 3 and 4 have methyl and _____ groups (though the placement of these groups in rings 3 and 4 is FLIPPED).
PYRROLE
METHENYL
CONJUGATED
Colored
Uncolored
Vinyl
Propionyl
delta-Aminolevulinic acid synthase (ALAS) is the enzyme that catalyzes the ____ step (which is the RATE LIMITING step) of Heme biosynth and requires Vit _____. A deficiency in Vit _____ leads to decreased ALAS activity and ______ ______ anemia.
FIRST
Vit B6
B6
MICROCYTIC HYPOCHROMIC anemia
Steps _____ and _____ in heme biosynth, catalyzed by the enzymes ______ ______ dehydratase and ________, respectively, can be inhibited by Pb. This would lead to a buildup of _______ and ______, respectively.
2
8
delta-AMINOLEVULINIC ACID dehydratase
FERROCHETOLASE
delta-AMINOLEVULINIC ACID
Zn-PROTOPORPHYRIN IX
There are 2 isoforms of ALAS (1 and 2.) ALAS 1 is present in _____ cells, and is feedback-inhibited by _____. ______ can be given as a therapy to basically block the pathway at this point, such that downstream intermediates don’t build up, which would otherwise lead to ______.
ALL
HEME
HEMIN
PORPHYRIA.
ALAS 2 is present in _____ cells (fetal liver; bone marrow), and its synthesis is stimulated by _____ or derepressed by ______.
ALAS 2 is present in ERYTHROID cells (fetal liver; bone marrow), and its synthesis is stimulated by IRON or derepressed by IRE-BP.
In the absence of enzyme 4, _________ III Synthase, HMB spontaneously converts to ________ I, which is converted to ________ I, moving down the “dead end” pathway.
In the absence of enzyme 4, UROPORPHYRINOGEN III SYNTHASE, HMB spontaneously converts to COPROPORPHYRINOGEN I, moving down the “dead end” pathway.
Uroporphyriniogen III decarboxylase converts the Acetyl groups on the four “corners” of heme to _____.
Methyl groups
Protoporphyrinogen IX is formed in the ______ via the enzyme ________ III Oxidase.
MITOCHONDRIA
COPROPORPHYRINOGEN III Oxidase.
In step 7, the enzyme _______ converts Protoporphyrinogen IX to ______ by oxidizing the ______ bridges. This generates _______ double bonds, which confers resonance and color.
The enzyme PROTOPORPHYRIN OXIDASE
PROTOPORPHYRIN IX
METHYLENE bridges.
CONJUGATED double bonds.
The final step in heme synthesis involves the enzyme _______, which can be inhibited by _____, resulting in __________ IX instead of heme.
It involves the enzyme FERROCHETOLASE, and it can be inhibited by Pb, resulting in Zn-PROTOPORPHYRIN IX.
Often, Porphyrias are genetic with a(n) __________ dominant mode of inheritance. Rarely, they can demonstrate a _______ recessive (in steps 2 and 4) or X-linked (recessive or dominant in ALAS2 - Step 1) mode of inheritance.
Often genetic with an AUTOSOMAL dominant mode of inheritance. Steps 2 and 4 can show AUTOSOMAL recessive inheritance, and step 1 can show X-linked inheritance.
Mutations in ALAS2 can cause either ________ anemia, which is X-linked _______, or _______ Protoporphyria, which is X-linked _______.
Can cause either SIDEROBLASTIC anemia, which is X-linked RECESSIVE, or ERYTHROPOEITIC Protoporphyria, which is X-linked DOMINANT.
Porphyria ______ _______ is the most common Porphyria; it arises from a mutation in enzyme 5, called _________, of the heme synthesis pathway. 80% of these cases arise from _____ damage as opposed to the 20% that are genetic with a(n) _______ dominant mode of inheritance.
Porphyria CUTANEA TARDA is the most common Porphyria; it arises from a mutation in enzyme 5, called UROPORPHYRINOGEN III DECARBOXYLASE. 80% of these cases arise from LIVER damage as opposed to the 20% that are genetic with an AUTOSOMAL dominant mode of inheritance.
Porphyria Cutanea Tarda symptoms are present in the ______ as a result of reactive ______ species generated by photoactivated porphyrinogens. Uroporphyrins accumulate in the ____, plasma, ____, and stool.
Present in the SKIN as a result of reactive OXYGEN species generated by photoactivated porphyrinogens. Uroporphyrins accumulate in the LIVER, plasma, URINE, and stool.
_______ _______ Porphyria is characterized by a mutation in _______ deaminase (_____ dominant) with _______ symptoms which can be sever. There’s no apparent skin disease because _______ haven’t been made in the pathway by this point. ALA and _______ build up in plasma and urine (urine darkens upon standing.)
ACUTE INTERMITTENT Porphyria is characterized by a mutation in PORPHOBILINOGEN deaminase (AUTOSOMAL dominant) with NEUROLOGICAL symptoms that can be severe. There’s no apparent skin disease because PORPHYRINS haven’t been made in the pathway by this point. ALA and PORPHOBILINOGEN build up in plasma and urine.
