Gene:on chromosome 3 at location: 156284651-156384186 ; length: 99536 ; type: protein coding

MME gene spans a region of 99536 bases and has 24 exons. Exons 1 and 2 encode 5 untranslated sequences. Initiation codon and transmembrane and cytoplasmic domain are encoded by exon 3, which has 170 bp. 20 short exons (exons 4-23) range in size from 36 to 162 bp. They encode large part of the extracellular portion of the enzyme. Exon 24 which has about 3400 bp encodes the COOH-terminal 32 amino acids and contains the entire 3 untranslated region (UTR). Exon 19 encodes the pentapeptide sequence associated with metalloproteinase zinc binding and substrate catalysis (His-Glu-Ile-Thr-His).
The sequence is nearly identical to rat and rabbit NEP.
Transcriptional regulation : MME is constitutively expressed in some tissues (kidney, adipose tissue, brain) and at some developmental stages in other (T- and B-lymphocytes, neutrophils). Its gene transcription is regulated by at least two alternative regulation regions including type 1 and type 2 promoter. Both regulatory regions are characterized by the presence of multiple transcription initiation sites and the absence of classic TATA boxes and consensus initiator elements. The purine-rich type 1 regulatory region, which includes 5 UTR exon 1 sequence, is characterized by multiple putative PU. l-binding sites and consensus ets-binding motifs. In marked contrast, the GC-rich type 2 regulatory region contains multiple putative Sp-l-binding sites, a potential consensus retinoblastoma control element (RCE); and an inverted CCAAT box. Type 2 promoter has a wide tissue distribution, a low constitutive level of expression, and multiple transcription initiation sites. However, normal and malignant lymphoid progenitors (fetal thymocytes and pre-B ALL) as well as fetal kidney and glioblastoma cell line A172 showed significantly higher levels of type 1 transcripts.

The 5 untranslated region of this gene is alternatively spliced, resulting in four separate mRNA transcripts. The coding region is not affected by alternative splicing. The transcript variants 1, 1bis, and 2a contain an alternate 5 UTR exon, compared to variant 2b. The 2b variant is the longest transcript and includes alternate exon 2b. Variants 2b, 2a, 1bis and 1 all encode the same protein.
Transcript variant 1 mRNA has 5643 bp. Transcript variant 1bis mRNA has 5619 bp. Transcript variant 2a mRNA has 5665 bp. Transcript variant 2b mRNA has 5710 bp.
In normal human tissues, the highest mRNA levels were found in kidney, prostate, liver, and lung. Other tissues with high levels include whole blood, bone marrow, thymus, skeletal muscle, brain, ovary, testis, and placenta. Levels in lymph nodes and other secondary lymphoid tissues are dependent on the content of CD10+ B-cells in secondary germinal centers.

MME belongs to peptidase family M13, which belongs to a peptidase superfamily known as the metzincins. These are zinc-dependent metallopeptidases. Family M13 also includes endothelin-converting enzyme 1 (ECE-1), Kell blood group glycoprotein, and peptidase O from Lactococcus lactis (gene pepO).

MME protein contains 750 amino acids, and is a type-II membrane anchored enzyme known to inactivate oligopeptides. It has a single 24-amino acid hydrophobic segment that could function as both a transmembrane region and a signal peptide. The COOH-terminal 700 amino acids compose the extracellular protein segment, whereas the 25 NH2-terminal amino acids remaining after cleavage of the initiation methionine form the cytoplasmic tail.

Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids. Biologically important in the destruction of opioid peptides by cleavage of a Gly-Phe bond. Involved in the degradation of atrial natriuretic factor.
Preferential cleavage of polypeptides between hydrophobic residues, particularly with Phe or Tyr at P1. Inhibited in a dose dependent manner by opiorphin. Inhibited by phosphoramidon and thiorphan.

Truncating mutations in the MME gene in mothers are the cause of alloimmunisation during pregnancy (1342 C to T nonsense mutation and 446delC). The absence of the MMP protein in pregnant women induces an alloimmunisation against MMP presented by fetus. Maternal antibodies attack fetal podocytes ensuing nephron loss, which could lead to chronic renal failure in early adulthood. This is the first model of idiopathic renal failure in early adulthood, which appears to be caused by immune-mediated fetal nephron loss.