Hydroxymethylbilane

This enzyme is also called porphobilinogen deaminase or hydroxymethylbilane synthase. 

Most of the subsequent steps of tetrapyrrole synthesis are identical in plants, animals, and bacteria. The pathway includes synthesis of the monopyrrole porphobilinogen from two molecules of ALA by the action of ALA dehydratase with the elimination of two molecules of water, followed by the assembling of a linear tetrapyrrole hydroxymethylbilane from fonr molecnles of porphobilinogen, ring closure and two modification reactions of side chains. This produces the first tetrapyrrole macrocycle, uroporphyrinogen HI. Therefore, eight molecules of ALA are necessary to form one tetrapyrrole. 

This enzyme [EC 4.3.1.8], also known as hydroxymethyl-bilane synthase, catalyzes the dipyrromethane-depen-dent reaction of four porphobilinogen molecules with water to produce hydroxymethylbilane and four molecules of ammonia. In the presence of a second enzyme, uroporphyrinogen-III synthase [EC 4.2.1.75], the product is cycUzed to form uroporphyrinogen-III. 

HMBS hydroxymethylbilane-synthase, Intermediaries heptacarboxy-, hexacarboxy-and pentacarboxyporphyrins, MIM Nr Mendelian Inheritance in Man number, PCT porphyria cutanea tarda, Proto protoporphyrin IX, PV porphyria variegata, Uro uroporphyrin... 

If the patient is actually asymptomatic, but has a family history of acute porphyria or prior symptoms suspicious of acute porphyria, hydroxymethylbilane synthase (HMBS) activity, plasma scanning, and fecal porphyrins should be measured. These tests will reveal AIP, P V, and HC. As a small percentage of AIP families exhibit normal HMBS activity, PBG in a urine sample can be added. PBG determination can also performed as a first choice, if an acute porphyria is suspected. But if normal, it does not exclude acute porphyrias in asymptomatic phases. Furthermore, the existence of an acute porphyria is only proved if the value exceeds at least five times the upper limit of normal. 

Table 7.3.8 Standards used in the determination of hydroxymethylbilane synthase activity...

An acute disease caused by a deficiency in hydroxymethylbilane synthase. 

Hydroxymethylbilane synthase 1 Hydroxymethylbilane Acute intermittent porphyria (AD,11q23) J... 

Fig. 34. The structure of uroporphyrinogen I (urogen I) and the conformation of hydroxymethylbilane which reacts to the spiro-intermediate 59. A = acetic acid side chain P = propionic acid side chain.

Figure 2 Biosynthesis of tetrapyrroles. 10, succinyl-CoA 11, glycine 12, 5-aminolevulinic acid 13, glutamyl-tRNA 14, porphobilinogen 15, hydroxymethylbilane 16, uroporphyrinogen III 17, chlorophyll a 18, heme a 19, coenzyme F430 20, vitamin 8 2 21, coenzyme...

Hydroxymethylbilane Synthase (EC 2.5.1.61), HMBS HMBS (also known as porphobilinogen [PEG] deaminase) is a cytoplasmic enzyme that catalyzes the formation of one molecule of the linear tetrapyrrole 1-hydroxymethylbilane (HMB also known as preuroporphyrinogen) from four molecules of PEG with the release of four molecules of ammonia. The former enzyme committee designation for HMBS was EC 4.3.1.8, but in 2003 the enzyme was redesignated as EC 2.5.1.61. The enzyme has two molecules of its own substrate PEG, attached covalently to the apoenzyme as a prosthetic group. The enzyme is susceptible to allosteric inhibition by intermediates further down the heme biosynthetic pathway, notably coproporphyrinogen-III and protoporphyrinogen-IX. 

Wright DJ, Lim CK. Simultaneous determination of hydroxymethylbilane synthase and uroporphyrino-gen-III synthase in erythrocytes by HPLC. Biochem J 1983 213 85-8. 

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