Brief description:

Similar to Human-GEM issues #665 and PR#677, all reactions should depend on one form of NH3/NH4+ and have the deprotonation reaction. Human-GEM resolved issue by removing all of the NH4+ versions and keep all of the NH3 version.

Unlike Human-GEM though, sticking with NH4 over NH3 would be preferable.
Reasons for NH4 over NH3:

From Mohiuddin SS, Khattar D. Biochemistry, Ammonia. [Updated 2023 Feb 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541039/

In nature, ammonia exists as both NH3 and in the ionic form of ammonia as ammonium ion (NH4+). A buffering reaction: NH3+ H+ --> NH4+ is used to maintain the relative amount of each form. Under biological conditions, the pKa of this reaction is about 9.15 and this reaction occurs almost instantaneously. As a result, the majority of ammonia under physiological conditions exists as NH4+, and only about 1.7% of total ammonia presents as NH3 at pH 7.4.

Most physiological scenarios for RBCs will have NH4 prevalent over NH3 due to the pH.

Current status:

Proposed status/to-do list:

• Update stoichiometry for 13DAMPPOX.
• Update stoichiometry for 2IMBUTDA.
• Update stoichiometry for 3MOXTYROX.
• Update stoichiometry for 42A12BOOX.
• Update stoichiometry for CSND.
• Update stoichiometry for CTPS1.
• Update stoichiometry for CYTD.
• Add NH4t as reversible transport by RHAG

Brief description:

From Thuillier L. Purification and kinetic properties of human erythrocyte Mg2+-dependent inorganic pyrophosphatase. Biochim Biophys Acta. 1978;524(1):198-206. doi:10.1016/0005-2744(78)90118-3:

Biosynthetic reactions which produce pyrophosphate (polysaccharides, proteins, DNA and RNA synthesis} are subject to a "thermodynamic pull" [1--3] due to the subsequent complete and irreversible hydrolysis of pyrophosphate by widely distributed pyrophosphatases (standard free energy of hydrolysis: AG ° = --23.56 kJ • mo1-1 of PPi in the absence of divalent cations[4]).

The following enzyme catalyzed reactions would be considered to be reversible:

• Orotate phosphoribosyltransferase, catalyzed by UMPS
• Nicotinamide phosphoribosyltransferase, catalyzed by NAMPT
• Hypoxanthine phosphoribosyltransferase, catalyzed by HPRT1

Current status:

Proposed status/to-do list:

• Reverse stoichiometry for ORPT.
• Set NMNS as reversible.
• Set HXPRT as reversible.

Brief description:

All reactions should depend on one form of H2S/HS(-) and have the deprotonation reaction. Issue can be resolved by removing all of the H2S versions and keep all of the HS(-) versions.

Reasons for HS- over H2S:

From Wang R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev. 2012 Apr;92(2):791-896. doi: 10.1152/physrev.00017.2011. PMID: 22535897.

The definition of what constitutes free sulfide, as opposed to bound sulfide, should also be noted. Free sulfide is dissolved H2S gas, which is a weak acid and in solution exists in the equilibrium H2S ↔ HS− ↔ S2−. With the pKa1 ∼7.0 and the pKa2 >17, there is essentially no S2− in biological tissues, nearly equal amounts of H2S and HS− within the cell, and approximately a 20% H2S/80% HS− ratio in extracellular fluid and plasma at 37°C and pH 7.4. Due to the temperature sensitivity of pKa1, the H2S/HS− ratio remains nearly constant in blood and tissues of ectothermic vertebrates over a wide range of body temperatures. For example, in trout blood at 10°C, the ratio is 15% H2S/85% HS−.

From Jennings ML. Transport of H2S and HS(-) across the human red blood cell membrane: rapid H2S diffusion and AE1-mediated Cl(-)/HS(-) exchange. Am J Physiol Cell Physiol. 2013 Nov 1;305(9):C941-50. doi: 10.1152/ajpcell.00178.2013. Epub 2013 Jul 17. PMID: 23864610; PMCID: PMC4042536.

The data indicate that HS(-) is a very good substrate for AE1; the Cl(-)/HS(-) exchange rate is about one-third as rapid as Cl(-)/HCO3(-) exchange. The H2S permeability coefficient must also be high (>10(-2) cm/s, half time <0.003 s) to account for the pH equilibration data.

Most physiological scenarios for RBCs will have HS- prevalent over H2S due to the pH, and Band 3 can exchange HS(-).

Current status:

Proposed status/to-do list:

• Update stoichiometry for H2SMT.
• Update stoichiometry for HTSULDHLA.
• Update stoichiometry for MTOX.
• Update stoichiometry for SPODM2.

Brief explanation of proposed change

Inclusion of additional references for G6PD. Studies explore G6PD-deficient RBCs

Affected items

Anything else:

Brief explanation of proposed change

Inclusion of additional references for CD36.

Affected items

Add the following publications as evidence for existing genes:

Anything else:

The current reaction uses proline instead of sarcosine as a substrate. This is erroneous. Easy to fix by replacing the proline metabolite with sarcosine