Search results for ALAD

Showing 13 results out of 13

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Protein (4 results from a total of 4)

Identifier: R-HSA-6801404
Species: Homo sapiens
Compartment: secretory granule lumen
Primary external reference: UniProt: ALAD: P13716
Identifier: R-HSA-6801397
Species: Homo sapiens
Compartment: ficolin-1-rich granule lumen
Primary external reference: UniProt: ALAD: P13716
Identifier: R-HSA-189453
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: ALAD: P13716
Identifier: R-HSA-6806504
Species: Homo sapiens
Compartment: extracellular region
Primary external reference: UniProt: P13716

RNA Sequence (1 results from a total of 1)

Identifier: R-HSA-5690895
Species: Homo sapiens
Compartment: cytosol
Primary external reference: ENSEMBL: ENST00000409155

Reaction (3 results from a total of 3)

Identifier: R-HSA-190141
Species: Homo sapiens
Compartment: cytosol
Lead binds to ALAD enzyme displacing half the zinc ions essential for its catalytic activity and inactivating it. Lead is a major environmental toxin and this enzyme is one of its principal molecular targets (Jaffe et al. 2001).
Identifier: R-HSA-189439
Species: Homo sapiens
Compartment: cytosol
5-Aminolevulinic acid dehydratase (ALAD aka porphobilinogen synthase, PBGS), catalyzes the asymmetric condensation of two molecules of ALA to form porphobilinogen (PBG). The substrate that becomes the acetyl side chain-containing half of PBG is called A-side ALA; the half that becomes the propionyl side chains and the pyrrole nitrogen is called P-ALA (Jaffe 2004). PBG is the first pyrrole formed, the precursor to all tetrapyrrole pigments such as heme and chlorophyll. There are at least eight bonds that are made or broken during this reaction. The active form of the ALAD enzyme is an octamer complexed with eight Zn2+ ions, four that are strongly bound and four that are weakly bound. The four weakly bound ones are dispensible for enzyme activity in vitro (Bevan et al. 1980; Mitchell et al. 2001).
Deficiencies of ALAD enzyme in vivo are associated with 5-aminolevulinate dehydratase-deficient porphyria (e.g., Akagi et al. 2000).
Identifier: R-HSA-5690886
Species: Homo sapiens
Compartment: cytosol
Iron and citrate are essential for the metabolism of most organisms so their regulation is critical for normal physiology and survival. Depending on cellular conditions, cytoplasmic aconitate hydratase (ACO1 aka iron regulatory protein 1, IRP1) can assume two different functions. During iron scarcity or oxidative stress, ACO1 functions as IRP1, binding to iron responsive elements (IREs) to modulate the translation of iron metabolism genes. In iron-rich conditions, IRP1 binds an iron-sulfur cluster (4Fe-4S) to function as a cytosolic aconitase. This functional duality of IRP1 connects the translational control of iron metabolising proteins to cellular iron levels.

During iron scarcity, ACO1 and iron-responsive element-binding protein 2 (IREB2) bind with high affinity to RNA stem-loops known as iron-responsive elements (IREs) present in the 5' untranslated region of the mRNAs of ferritin (composed of heavy and light subunits, FTH1 and FTL) and the erythroid form of aminolevulinic acid synthase (ALAD) and in the 3' untranslated region of the mRNA of the transferrin receptor (TFRC). Binding of ACO1 or IREB2 prevents translation of FTH1:FTL and ALAD and protects the mRNA of TFRC from degradation. ACO1 and IREB2 perform an important metabolic function in response to low intracellular iron levels by interacting with iron protein mRNAs to increase net iron uptake (via TFRC) and decrease sequestration (via FT) and utilisation (via ALAD) of iron (Kaptain et al. 1991, Philpott et al. 1994, Samaniego et al. 1994).

Glutaredoxin-3 (GLRX3) is essential for both transcriptional iron regulation and intracellular iron distribution. Silencing of human Grx3 expression in HeLa cells decreases the activities of several cytosolic Fe-S proteins, for example, iron-regulatory protein 1 (ACO1), a major component of posttranscriptional iron regulation. As a consequence, Grx3-depleted cells show decreased levels of ferritin and increased levels of transferrin receptor, features characteristic of cellular iron starvation (Haunhorst et al. 2013).

Set (1 results from a total of 1)

Identifier: R-HSA-5690884
Species: Homo sapiens
Compartment: cytosol

Complex (2 results from a total of 2)

Identifier: R-HSA-5690882
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-189400
Species: Homo sapiens
Compartment: cytosol

Person (1 results from a total of 1)

Authored Pathways: 0
Reviewed Pathways: 1
Authored Reactions: 0
Reviewed Reactions: 0

Pathway (1 results from a total of 1)

Identifier: R-HSA-189451
Species: Homo sapiens
Although heme is synthesised in virtually all tissues, the principal sites of synthesis are erythroid cells (~85%) and hepatocytes (most of the remainder). Eight enzymes are involved in heme biosynthesis, four each in the mitochondria and the cytosol (Layer et al. 2010). The process starts in the mitochondria with the condensation of succinyl CoA (from the TCA cycle) and glycine to form 5-aminolevulinate (ALA). The next four steps take place in the cytosol. Two molecules of ALA are condensed to form the monopyrrole porphobilinogen (PBG). The next two steps convert four molecules of PBG into the cyclic tetrapyrrole uroporphyringen III, which is then decarboxylated into coproporphyrinogen III. The last three steps occur in the mitochondria and involve modifications to the tetrapyrrole side chains and finally, insertion of iron. In addition to these synthetic steps, a spontaneous cytosolic reaction allows the formation of uroporphyringen I which is then enzymatically decarboxylated to coproporphyrinogen I, which cannot be metabolized further in humans. Also, lead can inactivate ALAD, the enzyme that catalyzes PBG synthesis, and ferrochelatase, the enzyme that catalyzes heme synthesis (Ponka et al. 1999, Aijoka et al. 2006).

The porphyrias are disorders that arise from defects in the enzymes of heme biosynthesis. Defective pathway enzymes after ALA synthase result in accumulated substrates which can cause either skin problems, neurological complications, or both due to their toxicity in higher concentrations. They are broadly classified as hepatic porphyrias or erythropoietic porphyrias, based on the site of the overproduction of the substrate. Each defect is described together with the reaction it affects (Peoc'h et al. 2016).
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